bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–03–01
58 papers selected by
Luca Bolliger, lxBio
  1. Next questions of autophagy in neurodegenerative diseases: From mechanisms to therapeutics.
  2. Amyotrophic Lateral Sclerosis (ALS) Genetics and Microbiota: A Comprehensive Review.
  3. Neuronal Cell-Cycle Re-entry Defines Divergent Outcomes Through Replication-Dependent DNA Damage in ALS.
  4. Microglial Senescence in Neurodegenerative Diseases: Mechanisms and Therapeutic Perspectives.
  5. Allicin improves motor neuron survival in amyotrophic lateral sclerosis by reducing neuroinflammation and modulating gut microbiota.
  6. Blood-brain Barrier Dysfunction in Parkinson's Disease: Mechanisms and Emerging Therapeutic Strategies.
  7. CD4+T cell metabolic reprogramming as therapeutic targets in neurodegenerative diseases.
  8. Autophagy induction mitigates FUS aggregate formation and early synaptic dysfunction at the NMJ in the FUS-ALS model.
  9. Targeting Autophagy, Ferroptosis, and Neuroinflammation: Polyphenol-Mediated Modulation of Emerging Signaling Pathways in Neurodegeneration.
  10. Cannabinoids, the Blood-Brain Barrier, and Neurodegeneration: Mechanisms, Dysregulation, and Therapeutic Perspectives.
  11. Current status and future prospects of brain-computer interfaces in the field of neurological disease rehabilitation.
  12. Adiponectin in neuroinflammation and parkinson's disease: A macromolecular and therapeutic perspective.
  13. 'Molecular and Cellular Neuroscience': Impacts of Eight Highly Cited Articles Published in This Section of Brain Sciences in 2024.
  14. Microglia heterogeneity and therapeutic strategies in Parkinson's disease.
  15. Holding but not folding: How a single charge flip uncouples the DNAJC7-Hsp70 relay in amyotrophic lateral sclerosis.
  16. Modeling stress-induced proteinopathies in Caenorhabditis elegans.
  17. TDP-43 pathology is linked to motor neuron loss but is independent of stress granules in vivo.
  18. Role of nuclear import proteins in maintaining proteostasis and disease pathogenesis.
  19. Advances and Challenges in the Use of Spinal Cord Organoids in ALS.
  20. Wild-type C9orf72 expression is a genetic modifier of C9-ALS survival.
  21. Preferences for Healthcare Delivery in Amyotrophic Lateral Sclerosis (ALS): A Survey of Patients and Caregivers in the United States.
  22. Mesenchymal Stem Cell-Based Therapies Applied in Neurological Diseases: A Systematic Review.
  23. Recent Advances in Nanoparticle-Based Drug Delivery Strategies to Cross the Blood-Brain Barrier in Targeted Treatment of Alzheimer's Disease.
  24. Intrathecal (G 4 C 2 ) 149 delivery in C9orf72-deficient mice yields mild motor dysfunction and ALS/FTD pathological hallmarks.
  25. Metabolic control of neuroinflammation: focus on itaconate and its derivatives in CNS disorders.
  26. Reprogramming brain-resident macrophages: from disease drivers to therapeutic allies in neurological disorders.
  27. Amyotrophic Lateral Sclerosis: The State of the Art on Treatments and the Therapeutic Role of the Intestinal Microbiome in Human Studies.
  28. Emerging Roles, Mechanisms, and Therapeutic Potential of Thyroid Hormones in Neurodegenerative Diseases: A Review.
  29. Safety and biodistribution of intrathecal administration of mesenchymal stem cells (MSCs) and neurotrophin-releasing nanoparticles in a porcine CSF-guided delivery model for amyotrophic lateral sclerosis (ALS) drug discovery.
  30. TRIM32-UBQLN2-p62 axis promotes TDP-43 inclusion formation and amyloid aggregation through shuttle condensates.
  31. Exploring the ALS Multistep Model.
  32. Exosome-Mediated Neuroprotection in Vascular Dementia: Mechanisms, Molecular Pathways, and Therapeutic Prospects.
  33. Modulation of the Kynurenine Pathway: A New Approach for Treating Neurodegeneration.
  34. Microglia-Neuron Crosstalk: An Intimate Molecular Conversation in Neurodegeneration.
  35. Disruption of BDNF signalling in neuropathologies.
  36. Absence of Neuromuscular Dysfunction in Mice with Gut Epithelium-Restricted Expression of ALS Mutation hSOD1G93A.
  37. Human CSF proteogenomics links genetic variation to neurodegenerative disease proteins.
  38. An Artificial Intelligence-Driven Multimorbidity Framework Reveals a Shared Metabolic and Immune Core Across Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia.
  39. Antisense Dipeptide Repeat Proteins Drive Widescale Purine Metabolism Aberration in C9orf72 Amyotrophic Lateral Sclerosis via ADA.
  40. Imaging-derived neuromuscular ultrasound phenotypes are associated with functional status in amyotrophic lateral sclerosis.
  41. Reversing Mitochondrial Dysfunction in Optineurin E50K Glaucoma: A Metabolic Approach to Neuroprotection.
  42. Clinical characterization of the proximal lower-limb ALS phenotype: a retrospective cohort study.
  43. Advances in cellular and structural engineering of brain organoids for disease modeling: A Comprehensive Review.
  44. PPAR-Delta Agonist Therapies Did Not Rescue Hallmark Disease Phenotypes in Two Sets of Preclinical Trials in ALS TDP-43 and C9orf72 Model Mice.
  45. Impact of Built-In Software Monitoring on Survival in Amyotrophic Lateral Sclerosis Patients Receiving Home Mechanical Ventilation: A Cohort Study.
  46. Classification of ALS molecular subtypes: a literature review on machine learning applications and their clinical value.
  47. Aging of the Blood-Brain Barrier and Altered Permeability to Peripheral Immune Cells: Implications for Central Nervous System Disorders.
  48. The role of dentists in the recognition of neurodegenerative and systemic conditions with neurological involvement.
  49. Investigating Properties of Palmitoylethanolamide in Physiology and Disease: Far Beyond an Anti-Inflammatory Shield.
  50. Exploring Sex-Based Mechanisms of Inflammation and Neurodegeneration in Multiple Sclerosis.
  51. Vedolizumab and the gut-CNS axis in multiple sclerosis: considering T cell licensing pathways.
  52. Malonyl-CoA Decarboxylase: A Spotlight on Brain Aspects.
  53. Blood Lactate as a Prognostic Biomarker for Survival and Weight Loss in Amyotrophic Lateral Sclerosis: An Exploratory-Validation Study.
  54. Intrathecal delivery of AAVrh10-mHexa combined with anti-inflammatory treatment reduces neuropathological markers and extends the lifespan of mice with early-onset Tay-Sachs disease.
  55. Cellular Aging Signatures in the Plasma Proteome Record Human Health and Disease.
  56. A Head-to-Head Comparison of AAV9 Biodistribution in Mice: Routes of Administration and Age Dependence.
  57. Reviewer Comment on Dallaire et al. "Mortality and Complications of Percutaneous Gastrostomy in Amyotrophic Lateral Sclerosis Patients".
  58. Circadian Disruption Through Light-Dark Cycle Alteration Induced Alzheimer's Disease-like Pathology in Mice.
  1. Innovation (Camb). 2026 Jan 05. 7(1): 100989
    Next questions of autophagy in neurodegenerative diseases: From mechanisms to therapeutics.
    Rongcan Luo.
      Autophagy, a key cellular degradation pathway, is central to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Despite progress in understanding its role, critical questions remain. This perspective highlights pressing issues, including cell-type-specific autophagy regulation, interactions with other cellular pathways, and challenges in translating autophagy-modulating therapies to clinical practice. Addressing these questions will advance our understanding of neurodegenerative diseases and pave the way for novel therapeutics.
    DOI:  https://doi.org/10.1016/j.xinn.2025.100989
  2. Int J Mol Sci. 2026 Feb 19. pii: 1978. [Epub ahead of print]27(4):
    Amyotrophic Lateral Sclerosis (ALS) Genetics and Microbiota: A Comprehensive Review.
    Mostafa Ahmed Kurdi, Hidayah Alotaibi, Asayel Tawfiq Alkhuraymi, Layyan Nassar Aldahery, Ali Fouad Alhawaj, Hamzah Jehad Aldali.
      Amyotrophic Lateral Sclerosis (ALS) is a severe, progressive neurodegenerative disorder characterized by the loss of upper and lower motor neurons, affecting 0.5 to 2.6 per 100,000 people, with a median survival of 2 to 5 years. It is increasingly seen as a multisystem disorder, sharing essential clinicopathological features with Frontotemporal Dementia (FTD). This convergence arises from overlapping molecular processes, including severe oxidative stress, glutamate-mediated excitotoxicity, mitochondrial dysfunction, and widespread aggregated TDP-43 proteinopathy in both sporadic and familial cases. Several key genetic factors have been identified, particularly mutations in C9orf72, SOD1, TARDBP, and FUS, which serve as important targets for novel treatments, such as Tofersen, a recently approved SOD1-specific antisense oligonucleotide (ASO) gene therapy. Additionally, there is increasing evidence of the gut-brain connection. Dysbiosis, involving species such as Akkermansia muciniphila, and lower levels of neuroprotective metabolites, such as nicotinamide, may affect the course of the disease. As a result, treatment strategies are shifting toward a personalized approach. This includes using gene therapy, ranging from ASOs and RNA interference (RNAi) to new CRISPR-based genome editing. It also involves exploring microbiome-modulating treatments, such as specific probiotics and Fecal Microbiota Transplantation (FMT). While microbiome and gene therapies remain largely experimental, their potential is promising, as highlighted by the recent approval of Tofersen. These novel approaches could be further enhanced and guided by more robust diagnostic criteria and by investigating early multimodal treatment strategies to slow the progression of this complex disease.
    Keywords:  amyotrophic lateral sclerosis; genetics; microbiota
    DOI:  https://doi.org/10.3390/ijms27041978
  3. bioRxiv. 2026 Feb 16. pii: 2026.02.13.705790. [Epub ahead of print]
    Neuronal Cell-Cycle Re-entry Defines Divergent Outcomes Through Replication-Dependent DNA Damage in ALS.
    Jonathan Plessis-Belair, Roger B Sher.
      Cell-cycle dysregulation has emerged as a shared mechanism of neuronal loss across neurodegenerative diseases (NDDs), including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease. In post-mitotic neurons, aberrant reactivation of cell-cycle signaling precedes degeneration, yet the upstream triggers and functional consequences of this process remain poorly defined. Nucleocytoplasmic transport (NCT) dysfunction, a hallmark of ALS and related disorders, disrupts the spatial distribution of key regulatory proteins and may contribute to maladaptive cell-cycle activation. Our recent evidence suggests that impaired nuclear import may initiate, rather than merely accompany, neuronal cell-cycle re-entry. Here, we show that cell-cycle activation in motor neurons distinguishes molecular subtypes and outcomes in ALS. We analyzed the AnswerALS transcriptomic cohort and identified a patient cluster characterized by robust upregulation of cyclins B and D. Clusters with lower levels of cell-cycle gene expression exhibited accelerated ALSFRS-R decline, whereas the highest cyclin-expressing cluster demonstrated comparatively improved functional trajectories over time. To test whether NCT disruption can mechanistically drive aberrant cell-cycle activation, we pharmacologically inhibited importin-β in human iPSC-derived spinal motor neurons. NCT disruption induced widespread proteomic mislocalization, including TDP-43 pathology, and triggered a transient wave of cell-cycle activity preceding neuronal death. Mechanistically, we identified DNA-replication initiation as a pathological event driving degeneration and demonstrated that selective inhibition of G1/S-associated CDK4/6 activity confers neuroprotection. Together, these findings link impaired nuclear import to maladaptive cell-cycle reactivation in neurons and highlight stage-specific engagement of the cell-cycle machinery as a determinant of neuronal vulnerability in ALS.
    DOI:  https://doi.org/10.64898/2026.02.13.705790
  4. ACS Chem Neurosci. 2026 Feb 24.
    Microglial Senescence in Neurodegenerative Diseases: Mechanisms and Therapeutic Perspectives.
    Yixiao Liu, Zexuan Hu, Yitong Xiao, Xinyuan Han, Xiaorui Cheng, Tianyuan Ye.
      The global aging population has led to a rising incidence of neurodegenerative diseases, casting a significant shadow on global health due to their complex and multifactorial nature. In addition to genetic predispositions, cellular senescence, particularly in microglia, the innate immune cells of the central nervous system, has become a significant contributor to neurodegeneration. In this review, we examine the mechanism of microglial senescence in neurodegenerative disease. We emphasize the need for continuous exploration of microglial senescence mechanisms and provide a future perspective for developing preventive drugs, encouraging researchers to develop new therapies for patients with neurodegenerative diseases.
    Keywords:  cellular senescence; microglia; neurodegenerative diseases; therapeutics
    DOI:  https://doi.org/10.1021/acschemneuro.6c00016
  5. Biochem Biophys Res Commun. 2026 Feb 19. pii: S0006-291X(26)00267-6. [Epub ahead of print]809 153503
    Allicin improves motor neuron survival in amyotrophic lateral sclerosis by reducing neuroinflammation and modulating gut microbiota.
    Ying Gao, Yanchao Lu, Shumin Zhao, Ranran Chen, Jialing Liu, Sutian Zhang, Xue Bai, Jingjing Zhang.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons (MNs). Allicin, a defensive molecule in garlic with anti-inflammatory and gut microbiota-modulating properties, has shown therapeutic potential in animal models of various diseases including Alzheimer's disease (AD). However, its possible therapeutic role in ALS remains unclear. The purpose of this study is to investigate the therapeutic effect of allicin in ALS transgenic SOD1G93A mice. Starting at 60 days of age, SOD1G93A mice received oral gavage of allicin (10 mg/kg) on alternate days, while the control group received an equal volume of normal saline (NS) on the same schedule. Twelve mice per group were used for monitoring disease onset and survival. Nissl staining and choline acetyltransferase (ChAT) immunofluorescence were used to quantify MNs in the anterior horn. Microglial activation was analyzed by immunofluorescence staining for Iba1, ARG1, and CD86. The mRNA expression levels of IL-10, TGF-β, IL-1β, and TNF-α were examined using qPCR. Additionally, fecal samples were collected for 16S rDNA sequencing to evaluate changes in gut microbiota composition. We observed that allicin treatment failed to prolong the onset time and survival period of SOD1G93A mice, but it extended the disease duration. Nissl staining analysis revealed that allicin treatment delayed the loss of spinal MNs, a finding corroborated by ChAT immunofluorescence. Furthermore, allicin treatment significantly reduced neuroinflammation and improved gut microbiota. Taken together, although allicin may prolong disease duration in ALS, it did not improve overall survival or delay disease onset. Therefore, its potential disease-modifying effects require further validation.
    Keywords:  Allicin; Amyotrophic lateral sclerosis; Gut microbiota; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153503
  6. Curr Neurovasc Res. 2026 Feb 19.
    Blood-brain Barrier Dysfunction in Parkinson's Disease: Mechanisms and Emerging Therapeutic Strategies.
    Gursimran Singh, Khadga Raj Aran.
       INTRODUCTION: PD is a progressive neurodegenerative disorder, which is associated with the deterioration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in motor and non-motor symptoms. Pathogenesis includes alpha-synuclein aggregation and Lewy bodies, neuroinflammation, and oxidative stress. The breakdown of the blood-brain barrier (BBB) via tight junctions and disturbed transporter activity has been identified as a factor in the evolution of PD.
    METHODS: The review is a synthesis of evidence provided by preclinical and clinical studies that examine the connection between BBB dysfunction and the pathogenesis of PD. PubMed, Web of Science, and Google Scholar were used to source the literature, and studies that show BBB permeability, α-synuclein pathology, and therapeutic interventions of BBB integrity were used as a limiting factor.
    RESULTS: Evidence indicates that the activation of BBB damage by disruptive activity allows the intrusion of neurotoxic factors and inflammatory agents in the central nervous system to worsen the degeneration of dopaminergic neurons. The changes in endothelial tight junction proteins, transporters, and immune cell infiltrations have remained consistent in PD models. Preclinical treatments, including neuroprotective therapeutics, anti-inflammatory medications, and treatments that alter the BBB permeability to be used in delivering drugs to specific brain locations, have demonstrated positive outcomes in the survival of neurons and motor activity.
    DISCUSSION: BBB dysfunction in PD appears to be an outcome and a cause of neurodegeneration, which forms a vicious cycle with neuroinflammation and α-synuclein deposition. Modifying permeability by targeting BBB repair pathways and selecting particular mechanisms to enhance permeability are promising disease-modifying therapies.
    CONCLUSION: BBB integrity is a very important but under-investigated element of PD pathogenesis. Understanding its interplay with neuroinflammation and protein aggregation may yield novel therapeutic targets and improve drug delivery approaches in PD management.
    Keywords:  Parkinson’s disease; astrocytes; blood-brain barrier; microglia; neuroinflammation; neurovascular unit.
    DOI:  https://doi.org/10.2174/0115672026434365260113100943
  7. Mol Brain. 2026 Feb 25.
    CD4+T cell metabolic reprogramming as therapeutic targets in neurodegenerative diseases.
    Prince Amoah Barnie, Karen Pomeyie, Benjamin Amoani, Foster Kyei, Abdala Ussif Mumuni, Justice Afrifa, Samuel Essien-Baidoo, Daniel Boison.
      Neurodegenerative diseases are a group of disorders characterized by the progressive loss of structure and function of neurons in the brain and/or peripheral nervous system. The main pathological feature of neurodegenerative disease in the central nervous system (CNS) is the selective neuronal loss in the brain and spinal cord, leading to cognitive and/or motor dysfunction. The immune system plays a variety of roles in the pathophysiology of neurodegenerative diseases. CD4+T cells are being recognized as important immunometabolic modulators in the pathophysiology of neurodegenerative disorders (ND), including multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD). Their varied metabolic patterns provide a special therapeutic window for regulating neuroinflammation, spanning from lipid-dependent regulatory T cells (Tregs) to glycolysis-driven pro-inflammatory subsets (Th1, Th17). Abnormal immune metabolism raises the risk of oxidative stress, mitochondrial malfunction, and neuronal death in neurodegenerative environments. According to recent research, altering CD4 T cell metabolism to favour oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) may help Treg function return and inhibit harmful effector responses. Current research on CD4 T cell immunometabolic pathways, their interactions with CNS-resident cells, and the developing possibility of metabolic intervention to slow neurodegeneration is explained in this review. By examining important signaling pathways including AMPK, mTORC1, and ROS dynamics, we demonstrate how CD4+T cell metabolism may reshape ND treatment approaches.
    Keywords:  Autoimmunity; CD4+T cells; Metabolic reprogramming; Neurodegenerative diseases; Treg
    DOI:  https://doi.org/10.1186/s13041-026-01282-6
  8. bioRxiv. 2026 Feb 20. pii: 2026.02.19.706635. [Epub ahead of print]
    Autophagy induction mitigates FUS aggregate formation and early synaptic dysfunction at the NMJ in the FUS-ALS model.
    Tulika Malik, Sam Jones, Olivia Ma, Sahana Mohan, R Michael Burger, Daniel T Babcock.
      Mutations in Fused in Sarcoma (FUS), a RNA binding protein, cause Amyotrophic Lateral Sclerosis (ALS). ALS is an aggressive neurodegenerative disease resulting in motor neuron degeneration. Defects in synaptic integrity precede neuronal loss in ALS, but the mechanisms responsible for these early synaptic defects are unclear. To investigate early synaptic defects associated with ALS, we expressed an ALS-linked variant of human FUS in adult motor neurons and assessed synaptic pathology at the neuromuscular junction (NMJ). Here we highlight the accumulation of FUS-positive aggregates at synaptic terminals and subsequent reduction in microtubule stability. We show that inducing autophagy via expression of Rab1 or Fragile-X Mental Retardation Protein 1 (FMR1), or treatment with Rapamycin reduces aggregate formation and restores synaptic structure and function. These findings reveal the utility of inducing autophagy to address early synaptic dysfunction in an ALS model and demonstrate a potential therapeutic target to preventing later stages of disease progression.
    DOI:  https://doi.org/10.64898/2026.02.19.706635
  9. Mol Neurobiol. 2026 Feb 26. pii: 470. [Epub ahead of print]63(1):
    Targeting Autophagy, Ferroptosis, and Neuroinflammation: Polyphenol-Mediated Modulation of Emerging Signaling Pathways in Neurodegeneration.
    Amulya Jindal, Sachchida Nand Rai.
      Complex, intertwined processes, including impaired autophagy, ferroptosis, and chronic neuroinflammation, drive neurodegenerative disorders (NDD). Polyphenols, a class of plant-derived natural compounds, are emerging as promising modulators of these pathogenic mechanisms, acting via diverse signaling pathways. This review summarized the molecular underpinnings of autophagy dysfunction, ferroptotic cell death, and inflammatory signaling in the central nervous system (CNS). Focusing mainly on key regulators such as AMPK, mTOR, Beclin-1, GPX4, NRF2, p62/Keap1, and system Xc⁻. Additionally, the evidence for polyphenol-mediated modulation of these pathways was also examined and covered in this study, along with highlighting compounds such as kaempferol, curcumin, resveratrol, epigallocatechin-3-gallate (EGCG), and many more. Polyphenols restore autophagic flux, suppress lipid peroxidation, restore redox balance, stabilizes mitochondrial function, and downregulate pro-inflammatory transcription factors (e.g., NF-κB, MAPKs). Furthermore, the interlink between autophagy and ferroptosis, such as ferritinophagy and lipophagy, as well as the dual roles of autophagy in either promoting or preventing ferroptosis depending on the cellular context, were also covered. The role of polyphenols in modulating these intersections to mitigate neuronal damage. Last, this review discussed the translational implications, including challenges in bioavailability, blood-brain barrier (BBB) penetration, and metabolic stability of polyphenols. Also, major potential therapeutic strategies include nanoformulations, targeted delivery, combinatorial therapies, and gaps such as timing, dosing, selectivity, and in vivo evidence in human disease. This review elucidates how polyphenols can harness emerging signaling nodes to yield novel therapeutic strategies for NDD by integrating insights across autophagy, ferroptosis, and neuroinflammation.
    Keywords:  Autophagy; Ferroptosis; Neurodegenerative disorders; Polyphenols; Signaling pathways
    DOI:  https://doi.org/10.1007/s12035-026-05760-9
  10. Biomolecules. 2026 Feb 02. pii: 225. [Epub ahead of print]16(2):
    Cannabinoids, the Blood-Brain Barrier, and Neurodegeneration: Mechanisms, Dysregulation, and Therapeutic Perspectives.
    Shimon Ben-Shabat, Ludmila Yarmolinsky, Nitzan Sharon, Taima Zeadnaa-Aldda, Shir Dayan, Boris Khalfin, Sigal Fleisher-Berkovich.
      Neurodegenerative diseases are a large and complex group of neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and so on, which adversely affect the physical and mental health of millions of people globally. Unfortunately, these diseases currently have no cure; only symptomatic treatment is available. Therefore, there is still a growing interest in using cannabinoids to treat neurodegenerative diseases. This systematic review examines the interrelationship between cannabinoids, the blood-brain barrier, and neurodegeneration, and their mutual effects. The objective of this review is to provide an overview of the endocannabinoid system at the neurovascular interface, the alterations and dysregulation of the ECS in neurodegenerative diseases, the interactions of phytocannabinoids with the blood-brain barrier, and their therapeutic potential in the context of neurodegeneration. The findings may facilitate the targeted application of cannabinoids to address multiple aspects of neurodegenerative diseases.
    Keywords:  blood–brain barrier; cannabinoids; neurodegeneration
    DOI:  https://doi.org/10.3390/biom16020225
  11. Front Rehabil Sci. 2026 ;7 1666530
    Current status and future prospects of brain-computer interfaces in the field of neurological disease rehabilitation.
    Yu Luo, Xiaohu Liu, Miaomiao Yang.
      Neurological disorders represent a significant category of diseases that profoundly affect human health, accounting for the second leading cause of global mortality. This group of conditions includes stroke, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury, Parkinson's disease, and cerebral palsy, among others. These disorders are highly susceptible to sequelae and profoundly impact individuals' daily lives. In this context, Brain-Computer Interface (BCI) technology has demonstrated considerable potential in the domain of neurorehabilitation, although numerous challenges remain. The manuscript provides a comprehensive review of recent advancements in research and clinical applications, highlighting current limitations and outlining future directions. It elucidates the applicability and constraints of Brain-Computer Interface (BCI) technology across various diseases and patient populations. To facilitate insights across different conditions, comparative tables are presented, aligning BCI strategies with therapeutic targets, outcomes, advantages, limitations, and existing evidence gaps. The scope extends beyond motor restoration to include under-explored domains, such as neuropathic pain, with a focus on real-world translation, including home and community feasibility and the distinction between assistive and rehabilitative applications. The review distills overarching limitations within the field, such as small sample sizes, protocol heterogeneity, and limited longitudinal evidence, while synthesizing the most recent studies. An actionable research and development roadmap is proposed to guide next-generation BCI rehabilitation, incorporating individualized cortical-network simulators, self-architecting decoders, adaptive therapy approaches akin to game seasons, and proprioceptive "write-back" mechanisms via peripheral interfaces. Moreover, the review reveals significant research focal points and critical issues that warrant further investigation in the context of neurological rehabilitation utilizing BCI technology.
    Keywords:  brain-computer interface; neuroplasticity; neurorehabilitation; non-invasive/minimally invasive treatment (NIMT); stroke
    DOI:  https://doi.org/10.3389/fresc.2026.1666530
  12. Metab Brain Dis. 2026 Feb 28. pii: 42. [Epub ahead of print]41(1):
    Adiponectin in neuroinflammation and parkinson's disease: A macromolecular and therapeutic perspective.
    Kanupriya Chauhan, Mayur Porwal, Shamsher Singh.
      Parkinson's Disease (PD) is a neurodegenerative disorder that exacerbates over time and is the result of long-term neuroinflammation and the degeneration of dopaminergic neurons. New research shows that adiponectin, an adipokine with strong anti-inflammatory and neuroprotective effects, could be a useful treatment for PD. This review explores molecular processes by which adiponectin changes important signaling pathways like AMPK, PPAR-γ, and NF-κB to lower oxidative stress, stop microglial activation, and improve neuronal survival. The article additionally addresses adiponectin-based treatments for PD, including as receptor agonists, bioengineered versions, and improved delivery systems. Transforming adiponectin-based treatments into practical applications is still difficult despite encouraging preclinical data because of things like blood-brain barrier permeability, ideal dosage, and possible systemic effects. Future studies should concentrate on creating pharmacological treatments, gene therapies, or adiponectin analogues that improve adiponectin signalling in the central nervous system. Novel insights into the pathophysiology of PD and potential treatment approaches may arise from an understanding of the interaction between metabolic control and neuroinflammation. The therapeutic promise of adiponectin is highlighted in this study, along with the necessity of additional research to fully utilise its neuroprotective properties in the treatment of Parkinson's disease.
    Keywords:  AMP-activated protein kinase; Adiponectin-based treatments; Dopaminergic neurons; NF-kB cascades; Neuroinflammation; Parkinson's disease
    DOI:  https://doi.org/10.1007/s11011-025-01769-6
  13. Brain Sci. 2026 Feb 04. pii: 188. [Epub ahead of print]16(2):
    'Molecular and Cellular Neuroscience': Impacts of Eight Highly Cited Articles Published in This Section of Brain Sciences in 2024.
    Swapan K Ray.
      This year, the selection criteria for highly cited articles in the 'Molecular and Cellular Neuroscience' section of Brain Sciences were focused on publications that achieved a citation count of 10 or more during 2024. Applying this metric, the Editorial Office, in collaboration with myself as Associate Editor of the 'Molecular and Cellular Neuroscience' section of the journal, identified eight articles that not only exemplified the mission of this section but also made significant scientific contributions by advancing our current understanding of the molecular and cellular mechanisms underlying major and rare neurological disorders. These articles encompass miscellaneous topics, including Alzheimer's disease (AD), chronic alcoholism, glioblastoma multiforme (GBM), amyotrophic lateral sclerosis (ALS), cognitive impairment, cerebrovascular disease, and Rett syndrome (RTT). Importantly, several contributions highlight experimental therapeutic strategies aimed at mitigating pathogenic mechanisms, offering promising avenues for translational research and future clinical applications.
    Keywords:  Alzheimer’s disease (AD); Rett syndrome (RTT); amyotrophic lateral sclerosis (ALS); cerebrovascular disease; cognitive deficiency; glioblastoma multiforme (GBM)
    DOI:  https://doi.org/10.3390/brainsci16020188
  14. Front Immunol. 2026 ;17 1739341
    Microglia heterogeneity and therapeutic strategies in Parkinson's disease.
    Jing Tian, Xuehui Liu, Zhuoqun Wang, Xue Shi, Chunlei Dai, Li Yang.
      Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and the abnormal aggregation of α-synuclein (α-syn). PD exhibits features of a chronic inflammatory disease, significantly affecting peripheral organs and the central nervous system (CNS). Clinical signs include motor symptoms such as rigidity, bradykinesia, and tremor, as well as non-motor symptoms such as psychological and cognitive issues. Microglia are resident immune cells of the CNS, exhibiting high heterogeneity and playing a crucial role in the neuronal degeneration and inflammation associated with PD. In PD, microglia play dual roles: maintaining PD homeostasis by phagocytosing and clearing α-syn aggregates while simultaneously becoming dysfunctional due to aggregate overload. This dysfunction drives their transition to a pro-inflammatory phenotype, exacerbating neurotoxicity. Recently, technological advances like single-cell transcriptomics have revealed the diverse functions and changing phenotypic lineages of microglia in PD, providing new insights into their mechanisms. This review systematically describes the biological traits of microglia and their functional, spatial, genetic, and gender-related differences in PD neurodegeneration. It summarizes new intervention and treatment strategies targeting microglia, highlights recent progress and challenges in preclinical research and clinical trials, and offers guidance for developing precision therapies for PD focused on modulating microglial function.
    Keywords:  PD; heterogeneity; immunotherapy; microglia; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1739341
  15. FEBS J. 2026 Feb 23.
    Holding but not folding: How a single charge flip uncouples the DNAJC7-Hsp70 relay in amyotrophic lateral sclerosis.
    Tsung-Sheng Chiang, Jerome Boisbouvier, Lauren A Gandy.
      Genetic mutations impact protein function through various routes: Some catalyze new oncogenic activities, while others trigger complete structural collapse. However, the E425K mutation in DNAJC7, associated with Amyotrophic Lateral Sclerosis (ALS), presents a far more subtle and intriguing case. In their recent study in The FEBS Journal, Elmaleh et al. (2026) FEBS Lett employed high-resolution NMR to demonstrate that this mutation leaves the protein's overall structure intact while selectively paralyzing its ability to communicate with the Hsp70 chaperone machinery. In this commentary, we show how their work complements in vivo studies that investigate ALS disease pathology at pathway complexity and defines a new target to rescue non-functioning Hsp70 chaperone systems.
    Keywords:  ALS; chaperone; foldase; holdase; methyl‐NMR; mutation
    DOI:  https://doi.org/10.1111/febs.70472
  16. Methods Cell Biol. 2026 ;pii: S0091-679X(25)00249-3. [Epub ahead of print]203 201-231
    Modeling stress-induced proteinopathies in Caenorhabditis elegans.
    Elena Caldero-Escudero, Silvia Romero-Sanz.
      Proteinopathies are a type of disorders characterized by the intracellular or extracellular accumulation of misfolded proteins that disrupt cellular proteostasis and exert toxic effects. These proteotoxic effects are a common hallmark of various age-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and polyglutamine disorders such as Huntington's disease (HD). Misfolded protein accumulation can impair numerous cellular processes, including mitochondrial function, protein degradation pathways, the endoplasmic reticulum stress response, and redox homeostasis, ultimately compromising cell viability. The nematode Caenorhabditis elegans (C. elegans) has emerged as a powerful model for studying proteotoxic stress due to its genetic tractability and the high degree of conservation of key cellular pathways when compared to mammals. These include mitochondrial dynamics and function, regulation of reactive oxygen species (ROS), and the cellular capacity to manage protein aggregates in terms of number, size, and clearance efficiency. The integration of these conserved stress response pathways together with C. elegans experimental versatility positioned this nematode as an ideal system to investigate the molecular mechanisms underlying proteinopathy-induced toxicity. In this chapter, we describe a set of complementary methodologies to evaluate proteotoxic stress in C. elegans models of protein misfolding. These include assays to measure mitochondrial reactive oxygen species (ROS) and membrane potential (Δψm), analyses of mitochondrial morphology and oxygen consumption, protein extraction protocols, and in vivo staining and semi-automated quantification of protein aggregates.
    Keywords:  Aggregates; C. elegans; Mitochondria; Proteinopathy; Protocols; Toxicity
    DOI:  https://doi.org/10.1016/bs.mcb.2025.12.007
  17. bioRxiv. 2026 Feb 13. pii: 2026.02.11.705439. [Epub ahead of print]
    TDP-43 pathology is linked to motor neuron loss but is independent of stress granules in vivo.
    Alicia Dubinski, Ala Ferdi, Mariam Choughari, Holly Spence, Arpita Adhikary, Carolane Fauchon, Melissa Touati, Myriam Gagné, Martha Liu, Sarah Peyrard, Jenna Gregory, Christine Vande Velde.
      Nuclear depletion and cytoplasmic aggregation of TDP-43 are pathological hallmarks of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease, and the recently defined limbic-predominant age-related TDP-43 encephalopathy (LATE). Chronic activation of the integrated stress response (ISR) and persistence of stress granules, phase-separated assemblies proposed to function as a protective mechanism, have been hypothesized to initiate the formation of pathological TDP-43 inclusions observed in post-mortem neurons. However, recent clinical trials targeting the ISR and stress granule dissolution failed to demonstrate clinical benefit despite robust target engagement, calling this model into question. Here, we employ a recurrent hyperthermia paradigm to directly examine the relationship between stress granules and TDP-43 pathology in vivo . We find that RNA-binding proteins classically associated with stress granules persist as phase-separated cytoplasmic structures in spinal motor neurons of both non-transgenic and mutant TDP-43 mice. Importantly, these structures are reversible and spatially distinct from TDP-43 puncta. Moreover, in a mutant TDP-43 mouse model with an impaired acute stress granule response, stress exposure induces TDP-43 nuclear export and cytoplasmic accumulation. Recurrent stress in these mice leads to a selective loss of spinal α-motor neurons. Together, our findings demonstrate that TDP-43 nuclear clearance and cytoplasmic demixing occur independently of stress granules in vivo , challenging prevailing models of TDP-43 pathogenesis and highlighting important implications for therapeutic strategies targeting the ISR.
    DOI:  https://doi.org/10.64898/2026.02.11.705439
  18. Biochem Pharmacol. 2026 Feb 20. pii: S0006-2952(26)00162-0. [Epub ahead of print]248 117831
    Role of nuclear import proteins in maintaining proteostasis and disease pathogenesis.
    Xiuling Zhao, Liping Pu, Xuhui Zeng, Junyu Nie.
      Nuclear import receptors (NIRs), particularly the importin α/β heterodimer system, function as essential gatekeepers of nucleocytoplasmic trafficking by decoding diverse nuclear localization signals (NLSs) to orchestrate cellular proteostasis. This review delineates the structural basis of NLS recognition and the coordinated mechanisms that facilitate the nuclear import of critical cargoes, including transcription factors, RNA-binding proteins, and DNA repair factors. Beyond their canonical transport role, we emphasize the emerging functions of NIRs as molecular chaperones that suppress aberrant phase separation and their co-translational regulatory roles in ensuring proper protein biogenesis and folding. The collapse of these regulatory functions underpins the pathogenesis of major human diseases. We examine in detail the pathological consequences of nuclear import dysfunction, highlighting its central role in specific neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), oncogenic transformation, and viral pathogenesis. The discussion provides a critical appraisal of emerging therapeutic strategies that target the nuclear import machinery, including small-molecule inhibitors (e.g., importazole, ivermectin), peptide competitors, and advanced delivery platforms. We conclude by providing the associated challenges such as achieving tissue specificity, avoiding off-target effects and the significant opportunities that lie in pharmacologically modulating this fundamental pathway to restore proteostasis and develop disease modifying therapies.
    Keywords:  Importin α/β; NLS; Nuclear import; Pathogenesis; Proteostasis
    DOI:  https://doi.org/10.1016/j.bcp.2026.117831
  19. J Integr Neurosci. 2026 Feb 26. 25(2): 44709
    Advances and Challenges in the Use of Spinal Cord Organoids in ALS.
    Yongxiang Zhang, Binghong Chen, Yuanxiang Lin, Dezhi Kang, Tong Zhao.
      Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease. No effective treatments have yet been found for ALS, primarily because the molecular mechanisms that underlie its pathogenesis are unknown. Although animal models are suitable for ALS research, species differences between these models and human spinal cord organs make it difficult to accurately predict the progression of disease in humans. Therefore, the development of more suitable models is urgently needed. Human stem cells have unlimited development potential and can be used to make three-dimensional organoid structures that mimic the architecture and function of actual organs. Organoid models can be used to overcome some of the species differences and accelerate experimental research, leading to the development of practical applications for the treatment of ALS. This article discusses the pathological mechanisms and cell types involved in ALS, as well as the genes associated with this disease. We also discuss the possible applications of spinal cord organoids (SCOs) in ALS research, such as the modeling of disease characteristics, study of pathological mechanisms, and drug screening. Finally, the prospects for SCOs in ALS treatment are highlighted, while acknowledging the need for further development of relevant technologies.
    Keywords:  amyotrophic lateral sclerosis; application; organoids; prospect; review; spinal cord
    DOI:  https://doi.org/10.31083/JIN44709
  20. medRxiv. 2026 Feb 09. pii: 2026.02.06.26345684. [Epub ahead of print]
    Wild-type C9orf72 expression is a genetic modifier of C9-ALS survival.
    Answer ALS Consortium
      1 Amyotrophic lateral sclerosis (ALS) is highly heritable, yet the vast majority of cases lack an identifiable genetic cause and clinical progression remains largely unpredictable. To connect noncoding and rare genetic variation to disease phenotypes in a relevant cell type, we generated a multi-omic quantitative trait locus (QTL) atlas from 594 induced-pluripotent-stem-cell-derived human motor neuron lines (522 ALS patients, 72 controls). By mapping cis-QTLs for chromatin accessibility, splicing and gene expression from whole-genome sequencing, we identify common and rare variants on the wild-type C9orf72 allele that form regulatory haplotypes. These haplotypes influence C9orf72 expression levels in motor neurons and stratify C9-ALS patients into four subgroups; using clinical disease duration data and longitudinal ALSFRS-R scores, we show that these subgroups exhibit different survival trajectories, indicating that wild-type C9orf72 expression acts as a genetic modifier of disease duration. Beyond the C9orf72 locus, we detect ultra-rare intronic variants that create cryptic exons and structural and nonsense variants in established ALS genes, providing likely genetic explanations for disease in additional patients who previously lacked a molecular diagnosis. Our results show that QTL mapping in patient-derived motor neurons can reveal regulatory modifiers of progression and hidden pathogenic events in ALS, providing a framework for genetically informed risk attribution and patient stratification in complex neurological diseases.
    DOI:  https://doi.org/10.64898/2026.02.06.26345684
  21. Patient. 2026 Feb 27.
    Preferences for Healthcare Delivery in Amyotrophic Lateral Sclerosis (ALS): A Survey of Patients and Caregivers in the United States.
    Ilene L Hollin, Hristelina Ilieva, Piera Pasinelli, Laura Chisholm, Terry Heiman-Patterson.
       BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurological disease that leads to death within 2-5 years of diagnosis for more than 80% of people living with ALS (PLWALS). The American Academy of Neurology (AAN) developed practice parameters-general principles to guide clinicians in managing ALS-encouraging multidisciplinary care (MDC) but does not recommend specific healthcare delivery models. Three healthcare delivery models have evolved: a traditional model, a triage model, and a non-triage model. This study aims to describe preferences for and satisfaction with various models, among PLWALS and their caregivers (CALS), along with their perceptions of how their care aligns with AAN guidelines.
    METHODS: A cross-sectional observational study utilizing a web-based survey was distributed via email to PLWALS and CALS. Three multi-assessment questionnaires were developed and tailored for PLWALS, CALS, and former CALS. Best-worst scaling (object case) data were analyzed using a best-minus-worst approach and descriptive statistics were calculated from means, t-tests and chi-square.
    RESULTS: The combined sample included 378 respondents: 254 PLWALS (67.20%) and 124 CALS (32.80%; composed of 79 current caregivers [20.90%] and 45 former caregivers [11.90%]). The mean respondent age was 61.09 years (SD 11.1). The majority of the sample was white (92.86%), insured by Medicare (61.11%), and married/partnered (79.10%). Respondents preferred a non-triage model the most and a traditional model the least; 88.20% (CI: 84.92-91.49) were extremely likely to choose a non-triage model if given the choice and 83.12% (CI: 79.29-86.92) of respondents ranked non-triage as most preferred. A traditional model was ranked as the least preferred model in 75.28% (CI: 70.78-79.78) of respondents. The most important factors driving respondent preferences were ALS expertise and team-based care. Overall, respondents are satisfied with their care teams. PLWALS utilizing non-triage MDC models reported more adherence to quality care measures compared with those utilizing triage and traditional models.
    DISCUSSION: Respondent preference for non-triage models is consistent with the importance they place on the features of non-triage models. However, these findings should be understood in the context of our sample in which a large majority of respondents were receiving care via a non-triage model. To ensure ALS care delivery is patient-centered, practice parameters that aim to guide clinicians in managing ALS should provide more guidance to MDCs to deliver care aligned with patient preferences and values. Efforts should focus on sustainable financial models that can better facilitate non-triage models of care.
    DOI:  https://doi.org/10.1007/s40271-026-00807-4
  22. Biomedicines. 2026 Feb 21. pii: 475. [Epub ahead of print]14(2):
    Mesenchymal Stem Cell-Based Therapies Applied in Neurological Diseases: A Systematic Review.
    Ana Trabulo, Patrícia Sousa, Rui Alvites, Ana Colette Maurício.
      Background/Objectives: Neurodegenerative diseases (NDs) have a severe impact on patients' quality of life, and effective treatments remain limited. As the focus is on treating the symptoms, the root cause of the problem is commonly not addressed. Mesenchymal stem cells show an emerging potential due to the ability for self-renewal combined with their capability for differentiation into various cell lines, which makes them a strong candidate for regenerative therapies in general, and for application in neurological issues in particular. This article provides an overview of the safety, efficacy, and challenges associated with the use of mesenchymal stem cells (MSCs) and their derived secretome in clinical and preclinical models of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Methods: A systematic search was conducted on PubMed to identify published studies providing clinical and preclinical evidence on the use of MSCs in neurodegenerative disorders. Results: Overall, the literature consistently indicates that MSCs and their derivatives exert disease-modifying effects across multiple NDs. Across AD, PD, HD and ALS, preclinical studies uniformly report improvements in behavioural outcomes, attenuation of neuroinflammation, and neuroprotective effects, largely mediated by MSCs' paracrine signalling rather than direct cell replacement. Clinical studies to date consistently support the safety and feasibility of MSC-based therapies, while efficacy signals remain modest, heterogeneous and predominantly short-term, highlighting the need for larger, well-controlled trials. Conclusions: Integration of genetic engineering, preconditioning, and EV technology may represent an emerging therapeutic approach that may complement existing neuroregeneration treatments, offering a scalable and minimally invasive frontier to improve long-term clinical outcomes in patients with AD, PD, HD, and ALS.
    Keywords:  extracellular vesicles; mesenchymal stem cells; neurodegenerative diseases; regenerative medicine; secretome
    DOI:  https://doi.org/10.3390/biomedicines14020475
  23. Pharmaceutics. 2026 Feb 01. pii: 192. [Epub ahead of print]18(2):
    Recent Advances in Nanoparticle-Based Drug Delivery Strategies to Cross the Blood-Brain Barrier in Targeted Treatment of Alzheimer's Disease.
    Hoa Le, Giang T T Vu, Amos Abioye, Adeboye Adejare.
      The blood-brain barrier (BBB) is a major obstacle to the development of brain-targeted drug delivery systems, restricting greater than 98% of small molecules (<500 Da) and virtually all large-molecule drugs from entering the brain tissues from the bloodstream, resulting in suboptimal drug doses and therapeutic failure in the treatment of Alzheimer's disease (AD). However, the advent of nanotechnology has provided significant solutions to the BBB challenges, enabling particle size reduction, enhanced drug solubility, reduced premature drug degradation, extended and sustained drug release, enhanced drug transport across the BBB, increased drug target specificity and enhanced therapeutic efficacy. In corollary, a library of brain-targeted surface-functionalized nanotherapeutics has been widely reported in the current literature. These promising in vitro, in vivo and pre-clinical results from the existing literature provide quantitative evidence for the relative clinical utility of each of the techniques, indicating remarkable capacity for brain-targeted carrier systems; many of them are still being tested in human clinical trials. However, despite the recorded research successes in drug transport across the BBB, there are currently no clinically proven medications that can slow or reverse the progression of AD because most of the novel therapeutics have not been successful during the clinical trials. Therefore, the main option for the treatment of AD is symptomatic treatment using cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. Although these therapies help to alleviate symptoms of AD and improve patients' quality of life, they neither slow the progression of disease nor cure it. Thus, an effective disease-modifying therapy for the treatment of AD is an unmet clinical need. It is apparent that a deeper understanding of the structural complexity and controlling dynamic functions of the BBB in tandem with a comprehensive elucidation of AD pathogenesis are crucial to the development of novel nanocarriers for the effective treatment of AD. Therefore, this narrative review describes the contextual analysis of several promising strategies that enhance brain-targeted drug delivery across the BBB in AD treatment and recent research efforts on two major AD biomarkers that have revolutionized AD diagnosis, amyloid-beta plaques and phosphorylated tau protein tangle, as potential targets in AD drug development. This has led to the Food and Drug Administration (FDA)'s approval of two intravenous (IV) anti-amyloid monoclonal antibodies, Lecanemab (Leqembi®) and Donanemab (Kisunla®), which were developed based on the Aβ cascade hypothesis for the treatment of early AD. This review also discusses the recent shift in the Aβ cascade hypothesis to Aβ oligomer (conformer), a soluble intermediate of Aβ, which is the most toxic mediator of AD and could be the most potent drug target in the future for a more accurate and effective drug development model for the treatment of AD. Furthermore, various promising nanoparticle-based drug carriers (therapeutic nanoparticles) that were developed from intensive research are discussed, including their clinical utility, challenges and prospects in the treatment of AD. Overall, it suffices to state that the advent of nanotechnology provided several innovative techniques for overcoming the BBB and improving drug delivery to the brain; however, their long-term biosafety is a relevant concern.
    Keywords:  Alzheimer’s disease; amyloid-beta oligomer; amyloid-beta plaque; blood–brain barrier; brain-targeting ligands; drug transport; protofibrils; tau protein tangle; therapeutic nanoparticles; tight junctions
    DOI:  https://doi.org/10.3390/pharmaceutics18020192
  24. bioRxiv. 2026 Feb 11. pii: 2026.02.09.704060. [Epub ahead of print]
    Intrathecal (G 4 C 2 ) 149 delivery in C9orf72-deficient mice yields mild motor dysfunction and ALS/FTD pathological hallmarks.
    Katelyn A Russell, Amelia A Shahrabi, Suleyman C Akerman, Matthew D Byrne, Jeffrey D Rothstein, Davide Trotti, Brigid K Jensen, Aaron R Haeusler.
      A repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet existing mouse models incompletely engage spinal regions implicated in disease. Here, an adeno-associated virus encoding (G 4 C 2 ) 149 repeats was delivered via neonatal intrathecal injection, achieving widespread CNS expression with robust spinal cord targeting. This approach was applied to mice with graded loss of endogenous C9orf72 to interrogate both gain- and loss-of-function mechanisms. Longitudinal motor, behavioral, and pathological analyses revealed that repeat expression primarily drives mild, progressive muscle weakness, whereas coordination deficits were largely genotype dependent. Subtle gait abnormalities and hyperactivity were also observed. Within spinal motor regions, repeat-expressing mice exhibited dipeptide repeat protein accumulation, reduced NeuN-positive area, glial activation, and sparse phosphorylated TDP-43 pathology. Cross-domain correlations further linked repeat expression, spinal pathology, and motor dysfunction. Collectively, these findings establish that CNS-wide repeat expression combined with reduced C9orf72 produces a coherent, mild ALS/FTD model.
    DOI:  https://doi.org/10.64898/2026.02.09.704060
  25. Front Immunol. 2026 ;17 1726379
    Metabolic control of neuroinflammation: focus on itaconate and its derivatives in CNS disorders.
    Ying Wang, Shihui Liu, Weijie Zhu, Pengyu Hao, Jiacan Xu, Diqi Mai, Ran Chen, Haojie Han, Xuechen Bian, Bodong Wang.
      The activation of microglia, which are the resident immune cells of the central nervous system (CNS), underpins the pathogenesis of neuroinflammatory and neurodegenerative diseases. Metabolic reprogramming has recently been recognized as a critical mechanism that regulates microglial activation because distinct activation phenotypes are tightly coupled to specific metabolic profiles that shape their functional and inflammatory responses. Accumulating evidence indicates that microglia produce itaconate through the tricarboxylic acid cycle, and itaconate and its derivatives play key antioxidant and anti-inflammatory roles. Mechanistically, itaconate has a major impact on the metabolic processes and functional state of microglia by blocking the NF-κB signaling route, activating the Nrf2 signaling pathway, and inhibiting succinate dehydrogenase synthesis as well as NLRP3 inflammatory vesicle activation. Collectively, these actions confer significant protection against CNS disorders, including ischemic stroke, Alzheimer's disease, Parkinson's disease, and cerebral hemorrhage. Furthermore, structurally optimized itaconate derivatives exhibit enhanced pharmacokinetics and bioactivity. This review highlights the pivotal role of itaconate and its derivatives in microglial regulation, explores their therapeutic potential in neurological diseases, and outlines future research directions, with the aim of providing a theoretical foundation for novel metabolic interventions.
    Keywords:  central nervous system diseases; itaconate; metabolic control; microglia; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1726379
  26. Front Cell Neurosci. 2026 ;20 1726194
    Reprogramming brain-resident macrophages: from disease drivers to therapeutic allies in neurological disorders.
    Peng Zhao, Su-Yi Li, Qun Liu, Xiao-Chun Peng, Lian Liu, Fu-Yuan Yang, Chao Wang, Feng Qian, Feng-Ru Tang.
      Brain-resident macrophages (BRMs), including microglia and border-associated macrophages (BAMs), are the core immune sentinels of the central nervous system (CNS). They originate from early embryonic yolk sac and fetal liver progenitors and maintain their population throughout life via self-renewal. During neurodevelopment, microglia maintain neural network homeostasis by phagocytosing apoptotic neural precursors and pruning synaptic connections. In adulthood, they rapidly respond to infection, injury, or protein aggregation, which can both promote repair and exacerbate neurotoxicity. BAMs, located in the meninges, perivascular spaces, and choroid plexus, play a key role in boundary homeostasis and peripheral immune signal surveillance. Recent studies reveal that BRMs exhibit dual roles in Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), as well as ischemic stroke, traumatic brain injury, and radiation-induced brain injury: they can protect neurons by clearing pathological proteins or cellular debris, but persistent inflammatory responses may drive neurodegeneration. In AD, microglia clear Aβ plaques via triggering receptor expressed on myeloid cells 2 (TREM2) and ADGRG1 signaling, while BAMs regulate synaptic damage and cerebrovascular function through CD36-ROS and SPP1 pathways. In PD and HD, BRMs contribute to α-synuclein- and mutant huntingtin-related inflammatory responses. In MS, BRMs modulate the pro-/anti-inflammatory balance through antigen presentation and cytokine signaling. Based on these mechanisms, therapeutic strategies targeting BRM functions are emerging, including NLRP3 inflammasome inhibitors, TREM2 agonists, and interventions promoting microglial neuroprotective phenotypes. Future approaches aiming to precisely modulate BRM plasticity and their interactions with the peripheral immune system may transform these immune sentinels from "disease drivers" to "therapeutic allies," offering novel strategies for treating neurodegenerative diseases and brain injuries.
    Keywords:  border-associated macrophage; brain injury; brain-resident macrophage; microglia; neurodegenerative disease
    DOI:  https://doi.org/10.3389/fncel.2026.1726194
  27. Int J Mol Sci. 2026 Feb 08. pii: 1655. [Epub ahead of print]27(4):
    Amyotrophic Lateral Sclerosis: The State of the Art on Treatments and the Therapeutic Role of the Intestinal Microbiome in Human Studies.
    Ondřej Ptáček, Zdeněk Musil, Giulia Guarnieri, Alena Vrbacká, Pavla Moudrá, Aneta Zlámalová, Petra Röszlerová, Michal Tonhajzer, Vladimír Musil, Annamaria Morelli, Petr Zach.
      Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disorder; to date, there is no long-term effective treatment. Recently, a relationship has been discovered between the human intestinal microbiome and the pathogenesis of ALS, on which basis faecal microbiota transplantation (FMT) has been proposed as a potential treatment for ALS. In this review, we compare three existing case studies examining the effect of FMT on the course of ALS, highlighting differences in methodology and results. In two of the studies, a halt in the progression of ALS symptoms was observed following FMT, accompanied by improvement in patient health. However, in the third and largest study, no significant effect of FMT was observed. The possible explanation for this discrepancy may be the intentional depletion of intestinal microorganisms using antibiotics prior to FMT in the third study. Future studies and/or completion of the ongoing clinical studies will help clarify the therapeutic effectiveness of FMT in ALS patients.
    Keywords:  ALS; FMT; amyotrophic lateral sclerosis; faecal microbiota transplantation; gut microbiome; human; intestine
    DOI:  https://doi.org/10.3390/ijms27041655
  28. Brain Sci. 2026 Feb 14. pii: 229. [Epub ahead of print]16(2):
    Emerging Roles, Mechanisms, and Therapeutic Potential of Thyroid Hormones in Neurodegenerative Diseases: A Review.
    Xin'ai Li, Zhe Li, Manna Sun, Yunlong Du, Han Bai, Xiaoheng Chen, Junhui Wang.
      Thyroid hormones (THs) are master controllers in the endocrine system and have drawn considerable attention from the research community due to their associations with neurodegenerative diseases as well. In this review article, we present a comprehensive summary of the physiological functions and pathogenic mechanisms of THs in the regulation of several representative neurodegenerative diseases. Our study particularly focuses on Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). AD is the most common cause of dementia, primarily caused by tau protein tangles inside nerve cells and β-amyloid plaques outside, which lead to nerve cell death and brain atrophy. PD is primarily a movement disorder. The degeneration of dopaminergic neurons in the brain impairs the brain's control over muscle activity. MS is usually considered to be an autoimmune demyelinating disease, but it has been found that MS also presents with secondary neurodegenerative pathology, including axonal loss and neuronal damage. In this review, the effects of TH on the pathogeneses of AD, PD, and MS are discussed in detail, with a focus on the following potential mechanisms: neuroprotection, neurogenesis, oxidative stress, and inflammatory response. In addition, we conduct an in-depth review of the possible clinical applications of TH, TH analogs, and thyrotropin-releasing hormone (TRH) in the treatment of AD, PD, and MS based on recent preclinical and clinical studies. By integrating experimental, clinical, and epidemiological results on the effects of TH on neurodegeneration, the present review constructs a theoretical basis for the involvement of TH in the pathogeneses of these diseases in detail. We believe that this basis will be useful for clinical diagnosis and treatment.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; neurodegenerative diseases; neuroprotection; oxidative stress; therapeutic potential; thyroid hormones; thyrotropin-releasing hormone
    DOI:  https://doi.org/10.3390/brainsci16020229
  29. Sci Rep. 2026 Feb 27.
    Safety and biodistribution of intrathecal administration of mesenchymal stem cells (MSCs) and neurotrophin-releasing nanoparticles in a porcine CSF-guided delivery model for amyotrophic lateral sclerosis (ALS) drug discovery.
    Emilia Sinderewicz, Maria Dąbkowska, Anna Sarnowska, Joanna Staszkiewicz-Chodor, Dorota Mystkowska, Piotr Holak, Igor Drozd, Magdalena Chodkowska-Michalowska, Monika Rytel, Edyta Paczkowska, Marcin P Mycko, Boguslaw Machalinski, Katarzyna Jezierska-Wozniak.
      Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disorder that complicates the identification of effective therapeutic targets. The potential of stem cells and neurotrophins as promising candidates has become increasingly evident, owing to their neuroprotective and anti-inflammatory properties. In this study, a preclinical evaluation of the safety and biodistribution of mesenchymal stromal/stem cells (MSCs) combined with neurotrophin-releasing polyelectrolyte nanoparticles (NTs) was conducted in a porcine intrathecal delivery model relevant to ALS therapy development. Four groups of male pigs were administered saline with NTs, adipose-derived stem cells (ASCs) with NTs, Wharton's jelly-derived MSCs (WJ-MSCs) with NTs, or spinal puncture only. The safety of the treatment was assessed using magnetic resonance imaging (MRI), haematological and biochemical analyses, cerebrospinal fluid profiling, and histology. No adverse effects or significant systemic alterations were observed. It is noteworthy that C-reactive protein levels diminished following NT and NT-MSC administration, suggesting a systemic anti-inflammatory effect. The migration of MSCs was facilitated by cerebrospinal fluid, leading to their accumulation around the spinal cord and brain parenchyma. The present findings demonstrate short-term safety and biodistribution patterns following intrathecal administration of MSCs combined with neurotrophin-releasing nanoparticles in a large-animal model. These preliminary observations provide a pilot framework for future efficacy studies in disease-specific ALS models. This work establishes a translational platform for the development of future ALS therapies, with subsequent studies focused on efficacy testing in disease-specific models that more accurately reflect the slow, heterogeneous, multisystem nature of human ALS.
    Keywords:  Brain-derived neurotrophic factor; Cell therapy; Neurotrophin-3; Porcine animal model; Preclinical studies; Stem cells/Mesenchymal stromal cells
    DOI:  https://doi.org/10.1038/s41598-026-40196-0
  30. bioRxiv. 2026 Feb 13. pii: 2026.02.11.705390. [Epub ahead of print]
    TRIM32-UBQLN2-p62 axis promotes TDP-43 inclusion formation and amyloid aggregation through shuttle condensates.
    Ziyan He, Jiechao Zhou, Rongzhen Zhang, Fei Meng, David W Nauen, Juan C Troncoso, Paul F Worley, Wenchi Zhang.
      Aberrant protein aggregation is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), which share overlapping genetic and pathological features. Similar aggregates are increasingly recognized in Alzheimer's disease (AD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). However, it remains unclear whether a shared molecular pathway drives this pathological aggregation. Here, we report that the E3 ubiquitin ligase TRIM32, together with the shuttle factor UBQLN2 and the autophagy adaptor p62/SQSTM1, form condensates that depend on E3 ligase activity and a network of intermolecular interactions. These condensates act as scaffolds that capture UBQLN2 client proteins, including TDP-43 and ANXA11, and modulate their mobility. A unique hydrophobic loop within TRIM32's substrate-binding domain mimics low-complexity motifs in ANXA11 and TDP-43, enabling selective retention via competitive binding mediated by UBQLN2 STI1 domain. Moreover, TRIM32 condensates promote amyloid aggregation of TDP-43, an effect that is exacerbated by pathogenic UBQLN2 mutation. In brains from individuals with diverse neurodegenerative diseases, TRIM32 co-localizes with pathological phospho-TDP-43 (pTDP-43) inclusions, supporting a model in which TRIM32-driven condensates function as selective proteostasis sorting compartments that broadly contribute to TDP-43 proteinopathy.
    DOI:  https://doi.org/10.64898/2026.02.11.705390
  31. Brain Sci. 2026 Feb 18. pii: 236. [Epub ahead of print]16(2):
    Exploring the ALS Multistep Model.
    Andrew Eisen.
      ALS is a multistep disease, in which (epi)genetic, environmental, and age-related processes, including senescence, converge over decades to reduce resilience resulting in self-sustaining symptomatic disease. The multistep model visualizes five to six impactful events in sporadic ALS, but fewer in those carrying high-penetrance mutations, such as SOD1, FUS, or C9orf72 expansions. The timing, duration, and cumulative effects of specific steps are presumed to have individual variability but, the steps themselves are inferred since they have not been observed and remain agnostic as to biological identity. Nevertheless, the model gives an opportunity to integrate genetics, aging, environmental exposures, and systems-level vulnerability into a single framework. Acting as step modifiers, environmental exposures including trauma lower the threshold for step acquisition, accelerate the accumulation of steps, influence the anatomical site of disease onset, and unmask preclinical disease. Because ALS emerges from the gradual collapse of multiple layers of biological robustness, tackling a single pathway will be insufficient and the multistep model forces a reconsideration of therapeutic timing and strategies. Protection against early-life insults, anti-aging, and anti-senescent therapies may curtail step accumulation preventing ALS from exceeding threshold and disease manifestation.
    Keywords:  aging–senescence; amyotrophic lateral sclerosis; environment; multistep model; neurodevelopment
    DOI:  https://doi.org/10.3390/brainsci16020236
  32. Mol Cell Probes. 2026 Feb 19. pii: S0890-8508(26)00006-X. [Epub ahead of print] 102066
    Exosome-Mediated Neuroprotection in Vascular Dementia: Mechanisms, Molecular Pathways, and Therapeutic Prospects.
    Farzaneh Fazli, Samin Davoody, Nicole Vissers, Sanaz Bordbar, Reza Rahbarghazi, Mohammad Karimipour, Hamid Taiefi Nasrabadi.
      Exosomes, a specialized class of extracellular vesicles, exhibit significant therapeutic potential for neurological disorders. In particular for vascular dementia (VaD), the second most common form of dementia. VaD is characterized by cognitive and behavioral impairments, often linked to hippocampal damage resulting from its vulnerable vascular structure, which disrupts memory formation and retrieval. Secreted by various cell types within the central nervous system, exosomes mediate intercellular communication by transporting bioactive molecules. Growing evidence indicates that exosomes enhance synaptic plasticity, modulate neuroinflammation, inhibit apoptosis, and promote angiogenesis, supporting their therapeutic potential in VaD. Given the urgent need for effective treatments and the unique ability of exosomes to cross the blood-brain barrier (BBB) and deliver multi-targeted therapies, research in this field is critically important. It offers a viable pathway toward the development of disease-modifying interventions for a condition that is currently managed primarily through symptomatic treatment. This review summarizes current knowledge on the function of exosomes in the central nervous system, examines recent advances in exosome-based strategies for VaD, and discusses ongoing challenges and future directions for their clinical translation.
    Keywords:  Exosomes; Learning; Memory; Neurogenesis; Synaptic plasticity; Therapeutic Intervention; Vascular Dementia
    DOI:  https://doi.org/10.1016/j.mcp.2026.102066
  33. Life (Basel). 2026 Feb 03. pii: 266. [Epub ahead of print]16(2):
    Modulation of the Kynurenine Pathway: A New Approach for Treating Neurodegeneration.
    Julia K Banaszkiewicz, Anna Kukiełka, Elżbieta Kudyk, Łucja J Walczak, Katarzyna Wicha-Komsta, Mariola Herbet, Iwona Piątkowska-Chmiel, Grzegorz Nowicki, Carmen E Mielnik, Tomasz Kocki.
      Neurodegenerative diseases, such as Parkinson's and Alzheimer's, are becoming an increasingly serious challenge for modern medicine because of the significant increase in incidence and the narrow range of effective therapeutic strategies. In recent years, the kynurenine pathway, which is one of the main pathways of tryptophan metabolism, responsible for the synthesis of products that act oppositely in the CNS including neurotoxic (quinolinic acid) and neuroprotective products, has gained increasing recognition as a potential therapeutic target. Abnormalities in the production of these metabolites, causing a disruption of homeostasis in the CNS, often lead to the development of inflammation, which can cause oxidative stress or neuronal death. This paper aims to discuss strategies useful in modulation of the kynurenine pathway, based on increasing the production of neuroprotective metabolites and reducing the synthesis of neurotoxic compounds, as well as to outline the progress in preclinical and clinical studies and the challenges encountered in these studies, among others, in the search for new KP inhibitors. The pharmacological (IDO and KMO inhibitors) and non-pharmacological (physical activity, diet) strategies are discussed, as well as new approaches from combination and targeted therapies. Together with the results of preclinical studies, they demonstrate the high utility of this target in the treatment of neurodegeneration. Despite its promising activity, further key studies are needed to fully understand the mechanisms involved in metabolism, which may translate into increased efficacy of developed therapies in the future.
    Keywords:  kynurenic acid; kynurenine pathway; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/life16020266
  34. Int J Mol Sci. 2026 Feb 20. pii: 2011. [Epub ahead of print]27(4):
    Microglia-Neuron Crosstalk: An Intimate Molecular Conversation in Neurodegeneration.
    Shiqi Wang, Sichen Wang, Hongzhuan Chen, Jianrong Xu.
      Microglia are a unique cell population in the central nervous system (CNS) and serve as its resident immune cells. They have long been recognized for their critical contributions to CNS development and the maintenance of neuronal network health, particularly in the context of neuroprotection against neurodegenerative diseases. However, the mechanisms by which microglia interact with and influence neurons have remained largely unclear. Recent advances in genetics, pharmacology, and imaging technologies have begun to unveil the mechanisms underlying microglia-neuron communication. Here, from the perspective of microglia, we review the diverse direct and indirect pathways and key molecules through which microglia interact with neurons under both physiological and pathological conditions. This rapidly expanding knowledge is reshaping our understanding of neuron-glia physiology and pathology in neurodegenerative diseases.
    Keywords:  bioenergetics; crosstalk; inflammation; microglia; neurodegenerative disease; neuron
    DOI:  https://doi.org/10.3390/ijms27042011
  35. Biochem Soc Trans. 2026 Feb 25. pii: BST20253079. [Epub ahead of print]54(2):
    Disruption of BDNF signalling in neuropathologies.
    Aurélie Paulo-Ramos, Elena R Rhymes, David Villarroel-Campos, James N Sleigh.
      The vital role of brain-derived neurotrophic factor (BDNF) in neuronal development, synaptic plasticity, and neuroprotection has been explored for decades. Therefore, the expression, processing, and signalling activities of this neurotrophin, which is reliant upon TrkB and p75NTR receptors, have been well characterised in both health and disease. This review summarises the latest findings on BDNF dysregulation in neuropathologies. Indeed, across diseases of both the central and peripheral nervous systems, BDNF signalling is frequently disrupted, contributing to neuronal dysfunction and degeneration. Consequently, through direct or indirect enhancement of its expression and/or function, BDNF has proved to be a promising therapeutic target across many neurological conditions. However, the complexity of its regulation and interaction with several different receptors underpins the need for further research to deepen our understanding of BDNF disruption in neuropathologies and to achieve its therapeutic potential.
    Keywords:  amyotrophic lateral sclerosis (ALS); brain-derived neurotrophic factor (BDNF); neurotrophin; tropomyosin receptor kinase B (TrkB)
    DOI:  https://doi.org/10.1042/BST20253079
  36. Biomolecules. 2026 Feb 05. pii: 253. [Epub ahead of print]16(2):
    Absence of Neuromuscular Dysfunction in Mice with Gut Epithelium-Restricted Expression of ALS Mutation hSOD1G93A.
    Li Dong, Xuejun Li, Ang Li, Jianxun Yi, Yanan Vockery, Yan Chang, Zui Pan, Marco Brotto, Jingsong Zhou.
      Amyotrophic Lateral Sclerosis (ALS) is a devastating neuromuscular disorder characterized by the progressive loss of motor neurons and skeletal muscle, ultimately leading to respiratory failure and death, typically within 3-5 years following diagnosis. While the death of motor neurons is the pathological hallmark, ALS is increasingly recognized as a systemic disorder involving non-motor systems. Gastrointestinal dysfunction has been widely observed in both ALS patients and animal models. However, because gut abnormalities and neuromuscular degeneration are intertwined during ALS disease progression, it remains unclear whether these gut abnormalities are merely a consequence of neuromuscular degeneration or whether they play a crucial role in initiating it. In this study, we investigated whether an ALS-associated mutation expressed exclusively in the gut can directly affect neuromuscular function. We generated a novel transgenic mouse model, Gut-hG93A, which overexpresses the human ALS mutation hSOD1G93A specifically in the epithelial cells of the intestine at a level comparable to the endogenous mouse SOD1. We found that the specific overexpression of hSOD1G93A in gut epithelial cells did not cause abnormalities in the structure of the tight junctions or in gut permeability. Furthermore, there were no significant differences between Gut-hG93A and control mice regarding lifespan, body weight, or neuromuscular activities, including grip strength, daily travel distance and in vivo muscle contractility. These findings suggest that the ALS-associated hSOD1G93A mutation, when expressed solely in the gut epithelium, is not sufficient to initiate neuromuscular degeneration of systemic ALS-like pathology.
    Keywords:  Cre-Lox; amyotrophic lateral sclerosis (ALS); gut epithelium; human ALS mutation hSOD1G93A; intestinal permeability; muscle contractility; skeletal muscle; transgenic mouse
    DOI:  https://doi.org/10.3390/biom16020253
  37. medRxiv. 2026 Feb 22. pii: 2026.02.12.26345733. [Epub ahead of print]
    Human CSF proteogenomics links genetic variation to neurodegenerative disease proteins.
    Raquel Puerta, Pablo Garcia-Gonzalez, Itziar de Rojas, Maria Capdevila-Bayo, Claudia Olive, Alvaro Munoz-Morales, Paula Bayon-Bujan, Alejandro Valenzuela, Chengran Yang, Jigyasha Timsina, Menghan Liu, Sathyaseelan Chakkarai, Oscar Sotolongo-Grau, Berta Calm, Andrea Miguel, Ariadna Solivar, Laura Montrreal, Marta Martinez, Asif Khan, Feiyang Zhao, Natalia Tantinya, Maitee Rosende-Roca, Montserrat Alegret, Sonia Moreno-Grau, Maria Victoria Fernandez, Marta Marquie, Sergi Valero, Jose Enrique Cavazos, Pilar Sanz, Xavier Montalban, Lluis Tarraga, Bart Smets, Merce Boada, Sudha Seshadri, Muralidharan Sargurupremraj, Carlos Cruchaga, Amanda Cano, Alfredo Cabrera-Socorro, Agustin Ruiz.
      The cerebrospinal fluid (CSF) proteome offers a direct readout of central nervous system (CNS) biology but its genetic architecture remains incompletely defined. We conducted the largest single-site CSF genome-wide association study (GWAS) to date, analysing 7,092 SomaScan proteins in 1,259 individuals. Using a covariate-adjusted model including proteomic PCs and disease status, we identified 1,971 genome-wide significant pQTLs (954 cis, 971 trans), 1,409 of which replicated in an independent CSF dataset. We discovered 264 previously unreported loci, replicated 511 associations, refined 80 known loci, and 265 proxy-based associations. Using a previously published reproducibility framework, we show that robust discovery concentrates in reliable measurements, underscoring the importance of rigorous quality control. Enrichment analyses revealed immune/complement and extracellular matrix biology. Mendelian randomization prioritised causal proteins: PILRA, TREM2, IL34, CR2, SHARPIN and ERBB1 (Alzheimer's disease); BST1 and GPNMB (Parkinson's disease); STX6 (Creutzfeldt Jacobs disease); and ATXN3 and B4GALNT1 (Amyotrophic lateral sclerosis), providing a scalable framework for orthogonal target validation in neurodegeneration.
    DOI:  https://doi.org/10.64898/2026.02.12.26345733
  38. Biomedicines. 2026 Feb 16. pii: 444. [Epub ahead of print]14(2):
    An Artificial Intelligence-Driven Multimorbidity Framework Reveals a Shared Metabolic and Immune Core Across Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia.
    Meghna R Iyer, Benjamin Zhao, Xin He, David Camacho, Zihan Wei, Jennifer Deng, Cassie S Mitchell.
      Background/Objectives: Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) share molecular features yet differ clinically, suggesting underlying systems-level commonalities. We aimed to characterize shared and disease-specific multimorbidity architectures across AD, ALS, and FTD using an artificial intelligence-driven literature-based semantic network. Methods: We applied SemNet 2.0, constructed from over 35 million PubMed abstracts, to analyze disease and syndrome (DSYN) and pharmacological substance (PHSU) nodes. Nodes were ranked using HeteSim and mapped to a harmonized 13-category mechanistic ontology. We quantified pairwise disease intersections, ontology-level enrichment, rank similarity, and intersection-disease alignment, and constructed an integrated multimorbidity priority landscape integrating disease-specific and intersection-level hierarchies. Results: Across AD, ALS, and FTD, a convergent multimorbidity architecture centered on a shared metabolic and immune core was identified, accompanied by prominent neurobehavioral processes and intermediate systems including gastrointestinal, endocrine, hematological, hepatic, and sensory pathways. Disease-specific signatures shaped distinct vulnerability profiles within this shared structure, including cardiovascular enrichment in AD, neuromuscular and toxin-related pathways in ALS, and coupled neurobehavioral-metabolic features in FTD. PHSU patterns reinforced these findings, with centrally positioned compounds predominantly targeting inflammatory, metabolic, or neuromodulatory processes. Conclusions: These findings position AD, ALS, and FTD within a unified, AI-derived multimorbidity framework. This ontology-guided approach provides a computational, hypothesis-generating foundation for multimorbidity-aware biomarker discovery, risk stratification, and cross-disease therapeutic exploration in neurodegenerative disease.
    Keywords:  Alzheimer’s disease; amyotrophic lateral sclerosis; artificial intelligence; frontotemporal dementia; knowledge graph; machine learning; metabolic dysfunction; multimorbidity; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.3390/biomedicines14020444
  39. Int J Mol Sci. 2026 Feb 18. pii: 1953. [Epub ahead of print]27(4):
    Antisense Dipeptide Repeat Proteins Drive Widescale Purine Metabolism Aberration in C9orf72 Amyotrophic Lateral Sclerosis via ADA.
    Benjamin Hall, Lydia Castelli, Adrian Higginbottom, Jingxuan He, Ling-Nan Zou, Heather Walker, Miriam Yagüe-Capilla, Kari E Wong, David J Burrows, Jonathan George, Keaton Hamer, Jenny M Tanner, Ergita Kyrgiou-Balli, Rees Ross, Herbie Garland, Erin Tonkiss, Rachel George, Christopher P Webster, Emma F Smith, Hannah O Timmons, Jess Allsop, Nikolas Stefanidis, Billie D Ward, Ya-Hui Lin, J Robin Highley, Mimoun Azzouz, Ryan J H West, Sean G Rudd, Kurt J De Vos, Pamela J Shaw, Guillaume M Hautbergue, Scott P Allen.
      Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by the death of motor neurons leading to paralysis and death, generally 3-5 years post-symptom onset. The most frequent genetic cause of ALS is a hexanucleotide repeat expansion (HRE) in the chromosome 9 open reading frame 72 (C9orf72) gene, that has three major hypothesised pathological mechanisms including the production of dipeptide repeat proteins (DPRs). Our laboratory has previously identified purine metabolism dysfunction in induced neural progenitor cell-derived astrocytes (iAstrocytes) from C9orf72 ALS (C9-ALS) cases (C9-iAstrocytes), driven by loss of the enzyme adenosine deaminase (ADA). Here, we have demonstrated that loss of ADA along with changes to ecto-5'-nucleotidase and hypoxanthine-guanine phosphoribosyl transferase led to disruption in purine metabolite levels including purine dNTP output. These changes were recapitulated in patient CSF, whilst loss of ADA was recapitulated in patient white matter. Immunofluorescence also demonstrated purinosome formation dysfunction in C9-iAstrocytes. These changes are likely driven by DPRs as ADA loss was recapitulated in in vitro and in vivo DPR models. Finally, ADA levels could be recovered by reducing DPR levels either by inhibiting serine/arginine-rich splicing factor 1 or overexpressing RuvB-like 2. Our data demonstrate that DPR production negatively affects purine function in C9-ALS suggesting a potentially pivotal role for purine metabolism dysfunction in C9-ALS pathology.
    Keywords:  ADA; ALS; C9orf72; DPR; MND; astrocyte; metabolomics; purine metabolism; purinosome
    DOI:  https://doi.org/10.3390/ijms27041953
  40. J Neurol. 2026 Feb 21. pii: 158. [Epub ahead of print]273(2):
    Imaging-derived neuromuscular ultrasound phenotypes are associated with functional status in amyotrophic lateral sclerosis.
    Ying Wang, Hao Zhang, Tianhua Yang, Jialei Luo, Ting Lin, Xinyi Yan, Junlin Ding, Yuxuan Qiu, Min Zhao, Gaoyi Yang.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) presents with marked clinical heterogeneity, complicating diagnosis and management. Neuromuscular ultrasound (NMUS) provides a non-invasive means to visualize peripheral nerve and muscle integrity, but its potential to delineate ALS subtypes has not been systematically explored.
    OBJECTIVE: To identify clinically meaningful ALS subgroups through unsupervised clustering of NMUS features integrated with clinical and electrophysiological data.
    METHODS: A total of 454 ALS patients (August 2024-December 2025) underwent standardized NMUS assessment, including muscle thickness, echogenicity, and nerve cross-sectional area, alongside ALSFRS-R, manual muscle testing (MMT), and compound muscle action potentials (CMAPs). K-means clustering was applied to standardized NMUS variables, with cluster stability assessed using silhouette coefficients, sensitivity analyses (k = 2-5), and resampling-based adjusted Rand indices. Multivariable regression examined associations between cluster membership and ALSFRS-R.
    RESULTS: Two reproducible NMUS-based subgroups were identified: a Mild cluster (n = 288, 63.4%) and a Severe cluster (n = 166, 36.6%). The Severe cluster showed reduced muscle thickness and higher echogenicity across multiple sites, together with lower ALSFRS-R scores (adjusted β = - 3.84, 95% CI - 5.41 to - 2.27, P < 0.001). Cluster membership correlated negatively with MMT and CMAP amplitudes, supporting functional and electrophysiologic validity. Stability metrics confirmed robustness of the two-cluster solution.
    CONCLUSION: Integrating NMUS with clinical data enables objective, imaging-derived stratification of ALS patients into biologically and functionally distinct subgroups. This approach offers a pragmatic framework for phenotypic characterization and may inform personalized monitoring and trial design in ALS.
    Keywords:  ALSFRS-R; Amyotrophic lateral sclerosis; Neuromuscular ultrasound; Phenotypic heterogeneity; Unsupervised clustering
    DOI:  https://doi.org/10.1007/s00415-026-13705-4
  41. Res Sq. 2026 Feb 19. pii: rs.3.rs-8380062. [Epub ahead of print]
    Reversing Mitochondrial Dysfunction in Optineurin E50K Glaucoma: A Metabolic Approach to Neuroprotection.
    Bledi Petriti, Shobana Subramanian, Pete Williams, Kai-Yin Chau, Pawel Licznerski, Gerassimos Lascaratos, Soledad Aguilar-Munoa, Deborah Kamal, Haesoo Bae, Kambiz Alavian, David Garway-Heath, Elizabeth Jonas.
      Mutations in optineurin (OPTN) are linked to neurodegenerative diseases such as normal tension glaucoma (NTG) and amyotrophic lateral sclerosis. The E50K-OPTN mutation is the most common genetic cause of NTG, where it disrupts mitophagy and leads to the accumulation of dysfunctional mitochondria. To understand how cellular metabolism is altered in these persistent mitochondria, and whether any pathological state can be reversed, we investigated NTG-patient-derived fibroblasts carrying the E50K-OPTN mutation. We identified a form of mitochondrial leak metabolism driven by elevated levels of the ATP synthase c-subunit leak channel (ACLC). These cells exhibit reversed F1FO ATP synthase activity, increased mitochondrial proton leak, and fragmented mitochondria, resulting in inefficient oxidative phosphorylation and a shift toward aerobic glycolysis and high protein synthesis rate. The ratio of ATP synthase c-subunit to β-subunit was markedly elevated, suggesting open ACLC pores. Treatment with dexpramipexole normalized ATP synthase function and cellular metabolism, promoted ATP synthesis rather than hydrolysis and reduced protein synthesis rates. Dexpramipexole reduced p62 levels in E50K fibroblasts, consistent with a reduced mitophagic burden from decreased accumulation of damaged mitochondrial cargo. These findings identify ACLC-mediated leak as a central driver of metabolic dysfunction in E50K-OPTN glaucoma and suggest ACLC closure as a viable therapeutic strategy.
    DOI:  https://doi.org/10.21203/rs.3.rs-8380062/v1
  42. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Feb 24. 1-4
    Clinical characterization of the proximal lower-limb ALS phenotype: a retrospective cohort study.
    Alexandre Montalvo, Marta Gromicho, Miguel Oliveira Santos, Mamede de Carvalho.
      This study characterizes a rare phenotype of Amyotrophic Lateral Sclerosis (ALS) presenting with predominant proximal lower limb weakness at onset, a presentation often mimicking myopathy. We retrospectively reviewed 1980 patients, identifying 15 (0.75%) with this atypical onset. The majority were males (73%) with a median age of onset of 58.7 years. Approximately half presented with symmetric proximal lower limb weakness. Nine of the 11 tested patients had higher CK. Follow-up (median 53.7 months) revealed that 6 patients maintained isolated lower limb weakness for a median of 60.1 months, while others progressed to upper limbs or bulbar regions. NSG sequencing (in nine patients) identified mutations in three patients (SOD1, VAPB, and C9ORF72). This pattern poses a diagnostic challenge. While limitations include a small sample size and retrospective design, the findings highlight a heterogenous but often slow-spreading and benign course for this specific ALS subtype, offering valuable clinical information for differential diagnosis.
    Keywords:  Amyotrophic lateral sclerosis; myopathy; phenotype; progression; proximal lower limb weakness
    DOI:  https://doi.org/10.1080/21678421.2026.2630882
  43. Tissue Cell. 2026 Feb 19. pii: S0040-8166(26)00093-5. [Epub ahead of print]101 103401
    Advances in cellular and structural engineering of brain organoids for disease modeling: A Comprehensive Review.
    Hyeongjoon Kim, Francis Joaquin Antonio Vasquez, Alvin Bacero Bello, Soo-Hong Lee.
       BACKGROUND: Organoid technology has rapidly evolved as a transformative tool for modeling human physiology and disease. Organoids are three-dimensional, stem cell-derived constructs that self-organize to recapitulate key structural and functional features of native organs. Among known organoids, brain organoids have provided unprecedented insights into human neurodevelopment and pathophysiology, overcoming the limitations of traditional two-dimensional cultures and animal models. These models closely mimic the architecture, cellular diversity, and regional specification of the human brain, offering a physiologically relevant platform for mechanistic studies. Therefore, brain organoids have become indispensable for investigating complex neurological disorders, such as Alzheimer's disease, Parkinson's disease, and schizophrenia.
    AIM OF THE REVIEW: This review aims to discuss recent advancements in brain organoid technology, emphasizing innovations in each component of the system: cells, supporting cells, three-dimensional architecture, and microenvironment, particularly in the context of major neurological diseases.
    KEY SCIENTIFIC CONCEPTS OF THE REVIEW: Notably, brain organoids provide valuable platforms for understanding molecular mechanisms, identifying therapeutic targets, and evaluating drug responses by preserving patient-specific genetic backgrounds and faithfully recapitulating disease-associated phenotypes. Meanwhile, advances in transcriptomic profiling, vascularization strategies, region-specific induction, and CRISPR/Cas9-based genetic engineering have further enhanced the utility and reproducibility of these techniques. This review summarizes key technological advancements and major findings in brain organoid research, including microenvironmental modulation, high-throughput culture platforms, and integrative analysis tools. We also highlight the associated applications in disease modeling, drug screening, and personalized medicine, while addressing current limitations and ethical considerations. As brain organoid systems continue to mature, through innovations such as assembloids, vascular integration, and patient-derived modeling, these systems offer great promise for bridging the translational gap in neuroscience and neurotherapeutics between bench and bedside.
    Keywords:  3D culture technology; 3D engineering; brain diseases; brain organoid; cell stems
    DOI:  https://doi.org/10.1016/j.tice.2026.103401
  44. Int J Mol Sci. 2026 Feb 13. pii: 1820. [Epub ahead of print]27(4):
    PPAR-Delta Agonist Therapies Did Not Rescue Hallmark Disease Phenotypes in Two Sets of Preclinical Trials in ALS TDP-43 and C9orf72 Model Mice.
    David T Luong, Chenchen Niu, Eunice Kim, Nolan Tanji, Ivy Duong, Brandon Galero, Yong-Jie Zhang, Craig L Bennett, Albert R La Spada.
      Peroxisome-proliferator-activated receptor delta (PPARδ) regulates metabolic, mitochondrial, and inflammatory pathways implicated in neurodegeneration, making it an attractive therapeutic target for amyotrophic lateral sclerosis (ALS). In this study, we evaluated two PPARδ agonists, KD3010 and T3D-959, in two established ALS/FTD mouse models: an AAV-mediated C9orf72 G4C2-repeat expansion model (C9-149R) and the TDP-43Q331K transgenic model. Drug treatment was initiated prior to the emergence of key disease features and continued for 9-10 months. Comprehensive behavioral, neuropathological, and biomarker analyses revealed marked differences between the two models. C9-149R mice exhibited reduced body weight and subtle behavioral alterations without robust motor deficits, whereas TDP-43Q331K mice developed pronounced, progressive motor and cognitive impairments accompanied by a ~7-fold elevation in plasma neurofilament light chain (NfL). Despite effective target engagement-particularly for T3D-959-neither PPARδ agonist improved motor performance, cognitive behavior, neuroanatomical measures, plasma NfL levels, or disease-associated molecular phenotypes in either model. Prolonged KD3010 treatment resulted in loss of target engagement, consistent with drug tolerance, while T3D-959 sustained PPARδ activation without therapeutic benefit. Together, these findings demonstrate that PPARδ agonism is insufficient to modify disease progression in these ALS/FTD mouse models and underscore the importance of publishing well-powered negative preclinical studies to refine therapeutic strategies for ALS.
    Keywords:  AAV-149R; C9orf72; KD3010; PPARδ; T3D-959; TDP-43; amyotrophic lateral sclerosis; dipeptide repeat; neurofilament light chain
    DOI:  https://doi.org/10.3390/ijms27041820
  45. J Clin Med. 2026 Feb 14. pii: 1513. [Epub ahead of print]15(4):
    Impact of Built-In Software Monitoring on Survival in Amyotrophic Lateral Sclerosis Patients Receiving Home Mechanical Ventilation: A Cohort Study.
    Ana Hernández-Voth, Javier Sayas-Catalán, Marta Corral-Blanco, Miguel Jiménez-Gómez, Gema Carvajal-Cuesta, Manel Luján-Torné, Cristina Lalmolda-Puyol, Pablo Florez-Solarana, Victoria Villena-Garrido.
      Background/Objectives: Amyotrophic lateral sclerosis is a progressive neurodegenerative disease in which respiratory failure is the leading cause of death. Mechanical ventilation improves both survival and quality of life; however, the prognostic implications of built-in ventilator software monitoring remain insufficiently characterized. The aim of the study was to determine whether built-in ventilator software-based monitoring is associated with enhanced survival in amyotrophic lateral sclerosis subjects. Methods: Cohort study of amyotrophic lateral sclerosis subjects, stratified into two groups: those monitored through detailed built-in ventilator software and those not monitored. Clinical and ventilatory data were systematically evaluated during a 24-month follow-up. Results: Among 120 ALS subjects (57 detailed built-in ventilator software, 63 non-detailed ventilator software), median survival from diagnosis was significantly longer in the detailed built-in ventilator software group (3.42 vs. 2.12 years; p < 0.001). Survival from mechanical ventilation initiation was also significantly longer in the built-in ventilator software group (2.79 years vs. 0.78 years). Greater daily mechanical ventilation usage was associated with shorter survival (p < 0.003). Paradoxically, subjects with the lowest proportion of spontaneous inspirations exhibited superior survival outcomes (p = 0.04). Neither persistent leaks nor asynchronies were independently predictive of survival. Conclusions: BVS-monitoring was associated with improved survival in amyotrophic lateral sclerosis subjects receiving home mechanical ventilation. Its integration into clinical practice may enable timely, data-driven ventilatory adjustments, ultimately contributing to more individualized and optimized patient management.
    Keywords:  amyotrophic lateral sclerosis; built-in-software; mechanical ventilation; prognosis
    DOI:  https://doi.org/10.3390/jcm15041513
  46. BMC Med. 2026 Feb 23.
    Classification of ALS molecular subtypes: a literature review on machine learning applications and their clinical value.
    John K Jammal, Esteban A Gomez, Ammar Al-Chalabi, Alfredo Iacoangeli.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by considerable heterogeneity in both its underlying biological mechanisms and clinical presentation. High-dimensional transcriptomic datasets offer an opportunity to characterise this variation at the molecular level; however, traditional statistical methods struggle with their scale and complexity.
    MAIN BODY: Machine learning approaches can reduce dimensionality and uncover latent patterns, enabling the identification of molecular subtypes that may refine prognosis and support patient stratification. Recent transcriptomic studies employing unsupervised machine learning have identified ALS subtypes with distinct molecular and clinical characteristics. Redefining ALS into more homogeneous molecular and clinical subtypes could transform all areas of ALS research by supporting novel experimental designs and precision medicine approaches.
    CONCLUSIONS: In this review, we summarise and critically assess these studies, discussing their findings, strengths, and limitations, and highlighting research gaps and challenges that must be addressed to enable their translation into biomedical and clinical practice.
    Keywords:  Amyotrophic lateral sclerosis; Glial cell activation; Machine learning; Molecular subtypes; Oxidative stress; Precision medicine; Transcription dysregulation; Transposable elements
    DOI:  https://doi.org/10.1186/s12916-026-04725-y
  47. Aging Dis. 2026 Feb 16.
    Aging of the Blood-Brain Barrier and Altered Permeability to Peripheral Immune Cells: Implications for Central Nervous System Disorders.
    Yu Gu, Liting Zhang, Zixin Du, Caiyun Wang, Wenyuan Deng, Yong U Liu, Beisha Tang.
      The blood-brain barrier (BBB), built by endothelial tight junctions, transporters, and the endothelial-pericyte-astrocyte unit, maintains a tightly regulated the central nervous system (CNS) milieu and permits selective immune cell entry. With age, tight junction downregulation, transport and metabolic imbalance, pericyte loss, basement membrane and glycocalyx remodeling, and reactive astrocytosis erode BBB integrity. These shifts reset leukocyte-trafficking thresholds and routes, producing either excessive admission or inadequate entry of peripheral immune cells. The resulting dysregulated immune surveillance activates microglia, amplifies neuroinflammation, disrupts myelin and synaptic homeostasis, and contributes to Alzheimer's and Parkinson's diseases, vascular dementia, and other neuroinflammatory conditions. This review synthesizes cellular and molecular mechanisms of BBB aging, outlines pathways and phenotypes of immune translocation, and proposes a cascade linking permeability imbalance to immune mismatch, driving neurodegeneration and injury. We discuss interventions focused on barrier repair and immune recalibration, including the reinforcement of tight junctions, restoration of pericyte homeostasis, and modulation of endothelial transport and chemokine axes. By implementing these strategies within stage- and time-specific therapeutic windows, this framework informs earlier diagnosis, biomarker development, and disease-modifying strategies for CNS disorders.
    DOI:  https://doi.org/10.14336/AD.2026.0013
  48. Oral Surg Oral Med Oral Pathol Oral Radiol. 2026 Jan 29. pii: S2212-4403(26)00017-9. [Epub ahead of print]
    The role of dentists in the recognition of neurodegenerative and systemic conditions with neurological involvement.
    Alberto Herrero Babiloni, Cibele Dal Fabbro, Firoozeh Samin, Matthieu Schmittbuhl, Pierre J Blanchet, Gilles J Lavigne, Guy Rouleau.
      Dentists are often the first healthcare providers to observe subtle orofacial and behavioral changes that may reflect underlying neurological diseases, including altered salivary flow, dysphagia, oral burning sensations, unusual orofacial movements, or tremors and pain, among others. These are symptoms of conditions such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, and other systemic disorders with neurological involvement, which are frequently misattributed to local or functional causes, thereby delaying diagnosis and care. As the frequency of neurodegenerative and neuromuscular conditions rises with aging, the dental setting offers a critical opportunity for early recognition and referral. This clinical review summarizes orofacial manifestations, dental care challenges, and referral strategies across different neurological and systemic diseases. Organized by disease stage and functional impairment, the review provides practical tools for decision-making. Guidance on screening, behavioral adaptation, and care coordination is also provided, including multiple practical tables, figures, and chairside screening tools to support early recognition and referral. Finally, the review advocates for improved training, interdisciplinary collaboration, and progressive integration of artificial intelligence, machine learning, and other emerging technologies (e.g., biosensors, salivary biomarker platforms, or high-density electrophysiologic tools) to support clinicians in recognizing neurological diseases.
    DOI:  https://doi.org/10.1016/j.oooo.2026.01.010
  49. Diseases. 2026 Jan 31. pii: 52. [Epub ahead of print]14(2):
    Investigating Properties of Palmitoylethanolamide in Physiology and Disease: Far Beyond an Anti-Inflammatory Shield.
    Chiara Veredice, Ida Turrini, Helena Pelanda, Ilaria Contaldo, Donato Rigante.
      Palmitoylethanolamide (PEA) among N-acylethanolamides displays a noteworthy impact on different inflammatory conditions and promises to become a valuable anti-inflammatory tool that does not interfere with the cyclooxygenase pathway. Mounting evidence confirms the multi-dimensional PEA-mediated crosstalk between microglia and mast cells, which would open new therapeutic opportunities targeting a neuroimmune axis and influencing both health and disease. In particular, PEA acts as a preserver of cellular homeostasis by regulating microglia cell activity and inhibiting mast cell activation in the central nervous system. The improved bioavailability and efficacy of ultramicronized formulations of PEA reflect its ultimate usefulness for different clinical applications, including significantly relieving inflammation but also reducing the pro-inflammatory burden of complex patients with either neuropathies or non-neurologic afflictions. This review aims to comprehensively delineate the therapeutic potential of PEA beyond its mere indication for acute inflammation and to highlight PEA activity as a broad-spectrum pan-tissue protective agent through the results of different preclinical and also some clinical studies. Much more remains to be learned about further PEA mechanisms of action that regulate neuroinflammation, and additional studies will have to investigate the exact role of microglia and mast cells in inflammatory diseases.
    Keywords:  N-acylethanolamide; bio-innovative therapies; chronic pain; endocannabinoidome; neurogenic inflammation; neuroinflammation; palmitoylethanolamide; personalized medicine
    DOI:  https://doi.org/10.3390/diseases14020052
  50. Biol Res Nurs. 2026 Apr;28(2): 283-295
    Exploring Sex-Based Mechanisms of Inflammation and Neurodegeneration in Multiple Sclerosis.
    Stephanie Buxhoeveden, Theresa Swift-Scanlan, Myla D Goldman, Ryan Canissario, Unsong Oh.
      Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by both immune-mediated inflammation and progressive neurodegeneration. While both processes occur in all individuals with MS, females more often present with heightened inflammatory activity, whereas males tend toward accelerated neurodegeneration and disability progression. This review synthesizes current evidence on biological, hormonal, genetic, epigenetic, and environmental mechanisms underlying sex-based differences in relapsing-remitting MS (RRMS), the most common MS subtype. We integrate findings from human studies, animal models, and molecular research to examine the contribution of genetics and epigenetic regulation including sex chromosomes, single nucleotide polymorphisms (SNPs), and microRNAs (miRNAs) to MS pathophysiology. We discuss the influence of sex hormones, including estrogen, progesterone, and testosterone, and environmental risk factors such as Epstein-Barr virus infection and vitamin D3 deficiency. Evidence suggests that X-linked immune-related genes, hormone - immune interactions, and sex-specific epigenetic regulation shape differential immune responses and neuronal vulnerability in males and females with MS. miRNAs emerge as critical molecular bridges linking genetic susceptibility, hormonal milieu, and environmental exposures to downstream inflammatory and neurodegenerative pathways. Understanding the mechanisms driving sex differences in MS may enable the development of targeted interventions addressing both neuroinflammation and neurodegeneration. Integrated miRNA - mRNA analyses, explicitly powered to assess sex as a biological variable, hold promise for identifying novel biomarkers and therapeutic targets. Such approaches could inform more personalized treatment strategies and improve long-term outcomes for all people with MS.
    Keywords:  MicroRNA; epigenetics; multiple sclerosis; neurodegeneration; neuroinflammation; sex differences
    DOI:  https://doi.org/10.1177/10998004251387318
  51. Ther Adv Neurol Disord. 2026 ;19 17562864261423751
    Vedolizumab and the gut-CNS axis in multiple sclerosis: considering T cell licensing pathways.
    Afsaneh Shirani, Olaf Stuve.
       Background: The role of gut-mediated T cell licensing in multiple sclerosis (MS) remains incompletely understood.
    Objective: We hypothesized that T cell licensing in the gut contributes to MS pathogenesis and evaluated whether vedolizumab-an anti-α4β7 integrin, gut-selective monoclonal antibody approved for inflammatory bowel disease (IBD)-is associated with MS prevalence.
    Design: Retrospective observational study.
    Methods: Using Epic Cosmos, a large deidentified U.S. electronic health record platform, we identified individuals with Crohn's disease (CD) or ulcerative colitis (UC) and a concomitant MS diagnosis between August 2010 and August 2025.
    Results: Among 1,027,704 CD and 1,294,362 UC patients, 8,098 (0.79%; 95%CI:0.77%-0.81%) and 9,564 (0.74%; 95%CI:0.73%-0.76%) had MS, respectively. In contrast, among vedolizumab-treated patients, only 125 with CD (0.22%; 95%CI:0.18%-0.26%) and 109 with UC (0.17%; 95%CI:0.14%-0.20%) developed MS within five years of treatment.
    Conclusion: While causality cannot be inferred, our findings highlight an opportunity to further explore whether vedolizumab-associated differences in MS prevalence may relate to gut-associated immune processes.
    Keywords:  T-cell trafficking; electronic health records (EHR); gut–brain axis; immune cell migration; inflammatory bowel disease (IBD); integrin α4β7; multiple sclerosis (MS); neuroimmunology; real-world evidence; vedolizumab
    DOI:  https://doi.org/10.1177/17562864261423751
  52. Brain Sci. 2026 Feb 12. pii: 220. [Epub ahead of print]16(2):
    Malonyl-CoA Decarboxylase: A Spotlight on Brain Aspects.
    Monique Fonseca-Teixeira, Elaine Silva Brito, Clara Beltrao-Valente, Bruna Klippel Ferreira, Patricia Fernanda Schuck, Gustavo Costa Ferreira.
      Malonyl-CoA decarboxylase (MCD) is an enzyme that controls malonyl-CoA levels and regulates fatty acid synthesis and oxidation. Although its physiological relevance in peripheral tissues is well known, the role of MCD in the central nervous system remains poorly understood. MCD is expressed in mitochondria, cytosol, and peroxisomes and may be regulated by PPAR-α, AMPK, and SIRT4 in tissues such as muscle, liver and kidney. In the brain, MCD expression varies during development and can respond to nutritional states. Inherited MCD deficiency (malonic aciduria) leads to the toxic accumulation of malonic acid and predominantly affects the central nervous system. The underlying mechanisms leading to brain damage in MCD patients remain unclear. Conversely, pharmacological modulation of MCD activity has been studied in obesity, diabetes, and ischemic injury, highlighting its therapeutic potential. There are still major gaps regarding MCD cellular distribution, regulatory pathways, and metabolic interaction with CPT1c (carnitine palmitoyltransferase 1c) in neural metabolism. A deeper understanding of the role of MCD in brain physiology and pathology may indicate novel therapeutic strategies targeting metabolic disorders that involve altered malonyl-CoA dynamics. Here, we discuss the current knowns and unknowns regarding MCD physiology, regulation, and pathophysiology, emphasizing brain aspects.
    Keywords:  brain; fatty acid metabolism; malonic acid; malonic aciduria; malonyl-CoA; metabolic disorders
    DOI:  https://doi.org/10.3390/brainsci16020220
  53. Ann Neurol. 2026 Feb 26.
    Blood Lactate as a Prognostic Biomarker for Survival and Weight Loss in Amyotrophic Lateral Sclerosis: An Exploratory-Validation Study.
    Ryutaro Nakamura, Frederik J Steyn, Shuhei Kobashi, Nobuhiro Ogawa, Akihiro Kitamura, Isamu Yamakawa, Robert D Henderson, Shyuan T Ngo, Makoto Urushitani.
       OBJECTIVE: Lactate is increasingly recognized as an energy substrate, but its relevance to amyotrophic lateral sclerosis (ALS) remains unclear. We examined whether blood lactate is associated with survival and weight loss in ALS.
    METHODS: This retrospective study included an Australian exploratory cohort and a Japanese validation cohort with clinical data matched to measures of blood lactate. The primary outcome was survival from onset to death or tracheostomy. In the exploratory cohort, survival was analyzed using Kaplan-Meier curves stratified by the first quartile (Q1) of lactate and multivariable Cox regression. This cutoff was applied for log-rank analysis in the validation cohort. The secondary outcome was 3-month body mass index (BMI) change (ΔBMI). Associations between baseline lactate and ΔBMI were assessed using multivariable regression in the exploratory cohort, whereas Q1-based stratification was used in the validation cohort.
    RESULTS: The exploratory cohort included 110 patients with ALS (57 with ΔBMI data) and 86 healthy controls; the validation cohort included 36 patients (17 with ΔBMI data). In the exploratory cohort, lower lactate levels (below Q1; 1.05 mmol/L) were associated with shorter survival (p = 0.031) and remained independently predictive of higher risk for mortality (adjusted hazard ratio [HR] per 1 SD = 0.57, 95% confidence interval [CI] = 0.35-0.91). This association was confirmed in the validation cohort (p = 0.003). Lactate was independently associated with ΔBMI (β = 0.53, p = 0.032), and patients with lower lactate had a greater BMI decline (p = 0.010).
    INTERPRETATION: Lower blood lactate is associated with increased risk for earlier death and greater weight loss in ALS, suggesting that lactate is a prognostic biomarker of nutritional status. ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78184
  54. Metab Brain Dis. 2026 Feb 25. pii: 39. [Epub ahead of print]41(1):
    Intrathecal delivery of AAVrh10-mHexa combined with anti-inflammatory treatment reduces neuropathological markers and extends the lifespan of mice with early-onset Tay-Sachs disease.
    Melike Can, Jerome Ausseil, Volkan Seyrantepe.
      Tay-Sachs disease is a lysosomal storage disorder caused by mutations in the HEXA gene, which encodes the α-subunit of β-hexosaminidase A-an enzyme that breaks down GM2 ganglioside. Recently, a mouse model of Tay-Sachs, the DKO, with deficiencies in both Hexa and Neu3 genes, showed severe neurological symptoms and neuroinflammation, surviving up to 20 weeks. In this study, we evaluated the therapeutic potential of intrathecal AAVrh10-mediated delivery of mouse Hexa, in combination with istradefylline treatment, in DKO mice. Using molecular, immunohistochemical, and behavioral methods, we found that the mice's lifespan increased to 30 weeks after receiving AAV alone or with istradefylline. Molecular analyses revealed increased Hexa activity, accompanied by reduced levels of the lysosomal marker Lamp-1 and pro-inflammatory cytokines, such as CCL2 and CCL3, in the cortex, cerebellum, and various organs, including the kidney, liver, and spleen. Immunohistochemistry revealed clearance of GM2 accumulation, fewer lysosomes, decreased active astrocytes, and improvements in neurons and oligodendrocytes in the brains of DKO mice. Correspondingly, their motor activity also improved. These results suggest that AAVrh10-based intrathecal delivery combined with istradefylline provides a promising therapeutic strategy for treating Tay-Sachs disease.
    Keywords:  AAV-based gene therapy; Istradefylline; Tay-Sachs disease
    DOI:  https://doi.org/10.1007/s11011-026-01802-2
  55. bioRxiv. 2026 Feb 12. pii: 2026.02.10.704909. [Epub ahead of print]
    Cellular Aging Signatures in the Plasma Proteome Record Human Health and Disease.
    Global Neurodegeneration Proteomics Consortium (GNPC)
      Aging is asynchronous across cells and organs, but whether plasma proteins can capture cell type-specific aging and predict disease and mortality remains unknown. We developed machine learning models to estimate the biological age of more than 40 distinct cell types-spanning neuronal, immune, glial, endocrine, epithelial, and musculoskeletal origins-using over 7,000 plasma proteins measured in 60,000 individuals across three cohorts, comprising the largest human plasma proteomics aging study to date. Individuals showed heterogeneous aging profiles, with 20-25% exhibiting accelerated aging in a single cell type and 1-3% across ten or more cell types. APOE genotype showed antagonistic aging effects in different cell types: APOE4 carriers exhibited older astrocytes but younger macrophages, while APOE2 carriers showed the inverse. Cellular aging signatures were uniquely associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Amyotrophic lateral sclerosis (ALS) showed the strongest association with skeletal myocyte aging (hazard ratio = 12.7 for extreme accelerated versus youthful aging). In Alzheimer's disease (AD), prevalent cases showed accelerated aging across multiple neural and peripheral cell types, with extreme astrocyte aging conferring AD risk comparable to APOE4 carrier status. Moreover, extreme astrocyte aging increased AD risk in APOE4/4 carriers threefold, while youthful astrocytes strikingly reduced risk. Beyond neurodegeneration, respiratory cell aging identified smokers at 58% higher lung cancer risk, and myeloid aging identified normoglycemic individuals at higher diabetes risk. Both specific cellular vulnerabilities and cumulative aging burden influenced survival, wherein youthful immune or neuronal profiles were protective. A polycellular aging risk score provided robust mortality risk stratification across platforms and cohorts. These findings establish a framework for quantifying biological aging at the cellular resolution using plasma proteomics, revealing heterogeneity in aging trajectories and their impact on disease susceptibility and resilience.
    DOI:  https://doi.org/10.64898/2026.02.10.704909
  56. Genes (Basel). 2026 Feb 09. pii: 213. [Epub ahead of print]17(2):
    A Head-to-Head Comparison of AAV9 Biodistribution in Mice: Routes of Administration and Age Dependence.
    Matthew Rioux, Andrea Boitnott, Satvik Paduri, Yuhui Hu, Steven J Gray.
       BACKGROUND/OBJECTIVES: Adeno-associated virus serotype 9 (AAV9) can cross the blood-brain barrier, making it widely used as a gene delivery vector for central nervous system (CNS) applications. Despite extensive use of AAV9 in translational research, variability in study designs makes cross-comparisons difficult to interpret. We designed a study in mice to generate a resource of AAV9 biodistribution across tissues for commonly used routes of administration and treatment ages.
    METHODS: Lumbar intrathecal, intracerebroventricular, lumbar intrathecal and intracerebroventricular combination, or intravenous injections of vehicle or AAV9/GFP were performed in C57BL/6J male and female mice on postnatal day 1, 5, 10, or 28. Organs were collected at postnatal day 56 and biodistribution of AAV9/GFP was evaluated by quantifying GFP protein expression and vector genome copy number.
    RESULTS: Direct cerebrospinal fluid injections led to higher transgene expression levels in the brain and spinal cord compared to intravenous administration but did not de-target transgene expression in peripheral tissues. Lumbar intrathecal and intracerebroventricular combination injections resulted in expression throughout the CNS but did not substantially increase expression in either the spinal cord or brain beyond the levels obtained with the respective single routes. Treatment age had effects on AAV9 biodistribution regardless of the route of administration, especially in the brain, eye, and liver.
    CONCLUSIONS: Our results provide the necessary biodistribution data to establish a standardized benchmark for comparison of the current gold standard AAV9 to next generation viral vectors. Additionally, this body of work can provide valuable insights for the design of translational gene therapy studies.
    Keywords:  AAV9; biodistribution; central nervous system; gene therapy; peripheral tissues; route of administration; treatment age
    DOI:  https://doi.org/10.3390/genes17020213
  57. Can J Neurol Sci. 2026 Feb 23. 1
    Reviewer Comment on Dallaire et al. "Mortality and Complications of Percutaneous Gastrostomy in Amyotrophic Lateral Sclerosis Patients".
    Jorge Carbó.
      
    DOI:  https://doi.org/10.1017/cjn.2025.10512
  58. Biomolecules. 2026 Jan 28. pii: 200. [Epub ahead of print]16(2):
    Circadian Disruption Through Light-Dark Cycle Alteration Induced Alzheimer's Disease-like Pathology in Mice.
    Guojie Zhao, Bo Cui, Yue Lu, Kefeng Ma, Xiujie Gao, Xiaojun She, Yingwen Zhu, Xiang Ji, Honglian Yang.
      Circadian disruption (CD) has emerged as a critical factor compromising human health in contemporary society. Increasing evidence suggests that disturbances in circadian rhythms are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). The hyperphosphorylation of tau and the deposition of amyloid-β (Aβ) are recognized as major pathological hallmarks of AD. In this study, we aimed to explore the impact of long-term CD on AD-like pathological changes and to explore the underlying molecular mechanisms using a mouse model. To mimic the CD experienced by shift workers, mice were subjected to lighting conditions involving repeated reversals of the light-dark cycle. In this study, qPCR was to employed detect the expression profile of clock genes in the hippocampus. Subsequently, Western blotting and immunohistochemical analyses were used to evaluate AD-like pathological changes in the hippocampus following CD. For elucidating the underlying mechanisms, we assessed circadian expression patterns of major neurotransmitters, activation of microglia and astrocytes, and alterations of tight junction proteins within the hippocampus. Our findings demonstrated that light-dark cycle disruption triggered CD in mice, and then CD led to increased expression of Aβ protein and tau hyperphosphorylation. CD significantly disrupted the circadian expression profiles of hippocampal clock genes and major neurotransmitters, induced microglial and astrocytic activation, and decreased the expression of the tight junction proteins zonula occludens-1 and occludin in the hippocampus. These results suggest that changes in the light-dark cycles induced abnormal expression of hippocampal clock genes involved in circadian rhythm regulation, suggesting that the body is in a state of endogenous CD. CD induces AD-like pathological changes in mice, potentially mediated by dysregulated circadian oscillations of clock genes, neuroinflammation, loss of key blood-brain barrier proteins, and disturbed neurotransmitter expression in the hippocampus. Collectively, this study underscores the importance of circadian stability for brain health, and highlights the necessity for deeper exploration into the connection between AD and CD.
    Keywords:  Alzheimer’s disease; amyloid-β deposition; blood-brain barrier; circadian disruption; clock genes; light-dark cycle; neuroinflammation; tau hyperphosphorylation
    DOI:  https://doi.org/10.3390/biom16020200
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