bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–04–19
fifty-two papers selected by
Luca Bolliger, lxBio
  1. Decoding RNA splicing pathology: Alternative splicing in amyotrophic lateral sclerosis and its therapeutic potential.
  2. Blood-brain barrier modulation for targeted central nervous system drug delivery in neurodegenerative and demyelinating disorders.
  3. Emerging strategies for interpreting variants of uncertain significance (VUS) in amyotrophic lateral sclerosis.
  4. Downregulation of miRNAs Accompanies Increased HERV-K (HML-2) Expression in Amyotrophic Lateral Sclerosis.
  5. The effect of statins on the survival of patients with amyotrophic lateral sclerosis: a meta-analysis.
  6. Elucidation of the influence of the CaV2.2 calcium channel on ALS disease progression in the SOD1*G93A mouse model.
  7. CAR Treg therapies for neurodegenerative diseases.
  8. A region-delineated snRNA-seq atlas of mouse spinal cord across lifespan resolves the interaction of normative aging programs with SOD1-G93A ALS.
  9. Beyond motor output: disrupted kinesthesia reveals hidden sensory-cognitive dysfunction in amyotrophic lateral sclerosis.
  10. Mechanisms underlying neuroimmune networks as central regulators in combating neurodegenerative diseases.
  11. Pharmacological interventions targeting the gut-brain axis in neurological disorders: mechanisms and translational applications.
  12. MAMs as a promising therapeutic strategy for age-related neurodegenerative diseases.
  13. Targeting Non-Coding RNAs as a Potential Therapeutic and Delivery Strategy Against Neurodegenerative Diseases.
  14. Speech-based digital endpoints track ALS progression and align with standard clinical outcomes: evidence from the VRG50635 trial.
  15. The neuroprotective effect of guanabenz combined with α-lipoic acid in the hSOD1-G93A amyotrophic lateral sclerosis model.
  16. Weight maintenance following enteral nutrition is associated with prolonged survival in amyotrophic lateral sclerosis.
  17. Outpatient versus inpatient initiation of home mechanical ventilation in patients with amyotrophic lateral sclerosis - a protocol for a randomised trial.
  18. MRI abnormal patterns of lumbar paraspinal muscles in patients with amyotrophic lateral sclerosis and lumbosacral radiculopathy: a comparative study.
  19. Discovery of a novel TFEB activator targeting lysosomal dysfunction in amyotrophic lateral sclerosis using artificial intelligence-based virtual screening.
  20. Genetic contributions to mitochondrial dysfunction in amyotrophic lateral sclerosis etiology.
  21. Dynamic changes in excitability and viability of sporadic and SOD1-related amyotrophic lateral sclerosis iPSC-derived motor neurons.
  22. Nose-to-brain delivery of a SOD1-stabilizing small molecule ameliorates pathology in an ALS mouse model.
  23. Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases.
  24. Sleep spindle alterations as a novel biomarker for phenotypic stratification in sporadic amyotrophic lateral sclerosis.
  25. An ALS-associated mutation in the C-terminal α-helix of TDP-43 uncouples condensate formation and amyloid assembly.
  26. Exploring the phenotypic spectrum of frontotemporal lobar degeneration.
  27. BrainShuttle-ESM: A Multi-Stage Transformer Architecture for Predicting Blood-Brain Barrier-Penetrating Short Peptides.
  28. Anti-Neuroinflammatory Cannabinoid Acids as a New Therapeutic Approach for Multiple Sclerosis.
  29. Development of a machine learning-based survival prediction model for ALS inclusive of the advanced-stage population.
  30. Dysregulated lactate metabolism synergizes with ALS genetic risk factors to accelerate motor decline.
  31. Pathogenesis and therapeutic strategies for neuropsychiatric lupus centered on innate immune activation.
  32. N-Acetylcysteine in Neurological Disorders: A Systematic Review of Clinical and Translational Evidence Across Seven Disorders.
  33. Simultaneous Expression of Sigma-1 Receptor and Tetraspanins Highlights Pathways of Receptor Sorting Into Extracellular Vesicles.
  34. Immune signaling and function in neurodegeneration.
  35. Multi-omics analysis of changes in the microbiota-gut- spinal cord axis in spinal cord injury.
  36. Autologous SVF therapy modulates neuroinflammation in ALS: phase I trial demonstrating safety and CSF biomarker dynamics.
  37. Erythrocyte Fragility in Progressive Multiple Sclerosis.
  38. Exploring the lung-brain axis in perioperative neurocognitive disorders: a potential therapeutic target.
  39. Involvement of the reticulospinal tract in the pathogenesis of spasticity after stroke and spinal cord injury.
  40. Irisin as a Regulator of Brain Energy Homeostasis: Implications for Age-Related Neurodegenerative Diseases.
  41. Nanomedicines for Neurodegenerative Ageing: Nasal Delivery Innovations for Alzheimer's and Parkinson's Disease.
  42. Extension of Lifespan and Amelioration of Alzheimer's Disease Phenotypes by Genetic Manipulation of Mitochondrial NAD+/NADH Ratio.
  43. Histamine H4 receptor in neuroinflammation: Dual roles in multiple sclerosis and Parkinson's disease.
  44. Gut microbiota and cognitive decline: a scoping review of microbial mechanisms and adaptive responses in dementia.
  45. Neurological manifestations of respiratory viral infections.
  46. The Dual Role of Microglia in Neurodegenerative Diseases: A Review.
  47. Tissue Context as a Determinant of Trained Innate Immunity: A Conserved Molecular Toolkit with Divergent Functional Outputs.
  48. Fast and controlled access to tofersen for SOD1-related amyotrophic lateral sclerosis in The Netherlands; experiences using the orphan drug access protocol.
  49. Disease-modifying treatment for multiple sclerosis in Poland in a European context: current practices and therapeutic strategies.
  50. Copper Dyshomeostasis Affects α-Synuclein Clearance Mechanisms in Parkinson's Disease: Insights from In Vitro Models and Translational Evidence.
  51. Effects of gut barrier dysfunction during a viral respiratory disease challenge on immune function of feedlot beef calves.
  52. Artificial intelligence revolutionizing CNS drug discovery and development.
  1. Biochem Biophys Res Commun. 2026 Apr 09. pii: S0006-291X(26)00487-0. [Epub ahead of print]818 153723
    Decoding RNA splicing pathology: Alternative splicing in amyotrophic lateral sclerosis and its therapeutic potential.
    Ratna Priya, Goutam Kumar Tanti, Buddhi Prakash Jain.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron loss, leading to muscle weakness, paralysis, and respiratory failure. Dysregulation of RNA metabolism and splicing has emerged as a central mechanism in ALS pathogenesis. TARDBP (TAR DNA-binding protein), FET family proteins (FUS, EWSR1, TAF15), SOD1 (Superoxide Dismutase 1), and C9orf72 (Chromosome 9 Open Reading Frame 72) are key genes associated with ALS that regulate RNA processing, alternative splicing, and nuclear-cytoplasmic transport. Mutations or mislocalization of these proteins result in nuclear loss-of-function and cytoplasmic gain-of-function toxicity, promoting protein aggregation, sequestering spliceosomal components, and impairing spliceosome assembly. This leads to the aberrant inclusion of cryptic exons in essential neuronal genes, such as STMN2 (Stathmin 2) and UNC13A (Unc-13 Homolog A), resulting in the production of truncated proteins, defective axonal maintenance, and impaired synaptic function. TDP-43 pathology, a hallmark of ALS, disrupts splicing and RNA transport, while C9orf72 repeat expansions and FET protein mutations exacerbate cytoplasmic aggregation and stress granule dynamics. Mutant SOD1 contributes via mitochondrial dysfunction, endoplasmic reticulum stress, and disrupted axonal transport. Therapeutic strategies targeting these mechanisms are advancing rapidly. Gene replacement therapy, which restores STMN2 expression, and antisense oligonucleotides (ASOs) targeting mutant transcripts show promise in preclinical and early clinical studies. Complementary approaches, including the inhibition of stress kinases and the activation of autophagy, reduce cytoplasmic protein aggregation and support neuronal homeostasis. This review provides a comprehensive overview of RNA splicing regulation, spliceosomal dysfunction, and cryptic exon incorporation in ALS. Understanding the interplay among splicing defects, RNA-binding protein pathology, and neuronal degeneration is critical for developing next-generation multimodal therapies to restore RNA processing, reduce toxic protein accumulation, and promote motor neuron survival.
    Keywords:  Alternative splicing; Amyotrophic lateral sclerosis; Exon; RNA binding proteins; RNA processing
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153723
  2. Tissue Cell. 2026 Apr 09. pii: S0040-8166(26)00217-X. [Epub ahead of print]101 103524
    Blood-brain barrier modulation for targeted central nervous system drug delivery in neurodegenerative and demyelinating disorders.
    Daniel Ejim Uti, Esther Ugo Alum, John Mathias Okpe, Josephine E Egbung, Jenavine Onyinye Mbah.
      The blood-brain barrier (BBB) plays an indispensable role in central nervous system homeostasis but it has remained a key barrier to successful treatment of neurodegenerative and demyelinating diseases. This review discusses the basis for BBB structural and functional regulation and critically discusses emerging strategies to improve therapeutic delivery in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and multiple sclerosis). Across pharmacological, nanotechnological, physical and genetic platforms, comes a common thread of ideas; rational and temporally-controlled BBB modulation is the uniting theme that underlies effective and safe brain-targeted therapy. Approaches such as receptor-mediated transcytosis, ligand-engineered nanocartiers, focused ultrasound with microbubbles, osmotic disruption, and electroporation or molecular or viral engineering have expanded the therapeutic landscape, but potential translational application relies upon reversibility, spatial selection, and preservation of neurovascular integrity. The discipline is shifting past proof-of-concept research to clinically-incrementally actionable paradigms anchored on pharmacokinetic accuracy, biomarker-directed goal involvement, and safety strict examination. The growing body of evidence has implied that bio-modulation of the BBB can augment the delivery of neuroprotective, anti-amyloid, anti-a-synuclein, and remyelinating therapeutic treatment with minimal systemic exposure and off-target damage. Together, BBB modulation is transitioning to become an experimental strategy of delivery, but with great clinical potential as a precision therapeutic strategy.
    Keywords:  Blood-brain barrier; Central nervous system; Drug delivery; Neurological illnesses; Permeability enhancement; Therapeutic potential
    DOI:  https://doi.org/10.1016/j.tice.2026.103524
  3. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Apr 16. 1-15
    Emerging strategies for interpreting variants of uncertain significance (VUS) in amyotrophic lateral sclerosis.
    Minhal Ahmed, Kathryn Volkening, Crystal Mclellan, Christen Shoesmith, Tugce B Balci, Michael J Strong.
      As the use of genetic testing for neurological diseases increases exponentially, interpreting variants of uncertain significance (VUS) has become a challenging problem. Nowhere has this become more evident than in amyotrophic lateral sclerosis (ALS) and the frontotemporal dementias (FTDs), both of which are complex heterogeneous disorders in which an increasing array of disease-causative and modifying genetic variants are observed. Moreover, while traditionally identified as distinct clinical syndromes, ALS and FTD are increasingly recognized to exist along a spectrum of clinical syndromes (termed the frontotemporal spectrum disorders of ALS; ALS-FTSD) with shared genetic risk. While VUS are generally not used in clinic for decision-making or counseling given their obvious limitations in being medically actionable, their correct interpretation is dynamic and rapidly evolving. VUS are increasingly the subject of intensive study as potential determinants of biological outcomes. It is timely therefore to review the current state of VUS interpretation and to critically evaluate how this can be applied to enhance both patient care and treatment decisions in the broader context of neurological disorders and more specifically in the context of ALS and ALS-FTSD. In doing so, we also explore the evolving challenge of defining pathogenicity of oligogenic inheritance in the context of multiple VUS detection in a single individual using an illustrative case example.
    Keywords:  VUS; genomics; neurodegeneration; oligogenic; optineurin; personalized medicine
    DOI:  https://doi.org/10.1080/21678421.2026.2655734
  4. Mol Neurobiol. 2026 Apr 17. pii: 570. [Epub ahead of print]63(1):
    Downregulation of miRNAs Accompanies Increased HERV-K (HML-2) Expression in Amyotrophic Lateral Sclerosis.
    Elena Rita Simula, Marta Garcia-Montojo, Mattia Canu, Vanna Chessa, Tommaso Ercoli, Elisa Ruiu, Paolo Solla, Avindra Nath, Leonardo Antonio Sechi.
      Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease with limited treatments. Evidence suggests that reactivation of the HERV-K (HML-2) subgroup contributes to its pathogenesis. This study explores the role of microRNAs (miRNAs) in regulating HML-2 expression. We identified dysregulated miRNAs in ALS and, among them, those predicted to target the HML-2 transcript. The expression levels of selected miRNAs were validated in peripheral blood leukocytes of ALS individuals and healthy controls. Co-transfection experiments were then performed to determine the regulatory potential of these miRNAs on HML-2 expression. We found that the HML-2 envelope gene expression levels were elevated in peripheral blood mononuclear cells of ALS individuals compared to controls (p = 0.02), and they negatively correlated with the levels of previously identified miRNAs, which were downregulated in patients compared to healthy controls (miR-15a-3p, p = 0.04; miR-15a-5p, p = 0.01; miR-150-5p, p = 0.001; miR-182-5p, p = 0.012; miR-192-3p, p = 0.034; miR-221-3p, p = 0.011), except miR-181a-2-3p that was upregulated in ALS compared to controls (p = 0.006). Among these miRNAs, we found, by co-transfection, that miR-182-5p and miR-221-3p were capable of binding the HML-2 transcript. This interaction resulted in a significant downregulation of the expression of its genes, with a pronounced effect observed on the envelope gene. Our findings suggest a link between miRNAs and HML-2 expression. In particular, the observed increase in HML-2 levels in ALS may result from the downregulation of key miRNAs, such as miR-221, that normally help restrain HML-2 expression under physiological conditions.
    Keywords:  ALS; Gene regulation; HERV-K; HML-2; MiRNAs; Neurodegeneration
    DOI:  https://doi.org/10.1007/s12035-026-05861-5
  5. Front Neurol. 2026 ;17 1753992
    The effect of statins on the survival of patients with amyotrophic lateral sclerosis: a meta-analysis.
    Hui Zhou, Ting Meng, Dan Liang, Yuanyuan Wang.
       Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited disease-modifying therapies and a poor overall prognosis. Statins, are commonly used for dyslipidemia, and have been proposed to exert cholesterol-independent actions including anti-inflammatory and potential neuroprotective effects. Prior studies, However, existing studies offer conflicting results regarding their impact on ALS survival. This systematic review and meta-analysis aimed to evaluate the association between statin use and survival outcomes in patients with ALS.
    Methods: A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science from inception to September 2025. Studies were included if they reported survival outcomes for statin users vs. non-users among patients with ALS. Data on hazard ratios (HRs) were extracted and pooled using fixed- or random-effects models, depending on heterogeneity. Meta-regression and sensitivity analyses were performed to explore the influence of covariates such as age and gender.
    Results: Six studies with 3,739 participants (889 statin users) met the inclusion criteria. The pooled analysis showed no statistical significant association between statin use and ALS survival [Log(HR) = -0.04; 95% CI: -0.18 to 0.10], with moderate heterogeneity (I 2 = 24.85%).
    Conclusion: The pooled estimate in this meta-analysis did not show a statistically significant association between statin use and ALS survival; however, the evidence is limited by heterogeneity in statin exposure definitions and likely residual confounding in predominantly observational data. Further high-quality studies with large sample sizes are needed to determine whether specific subgroups may benefit/harm from statin therapy.
    Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251160344; PROSPERO: CRD420251160344.
    Keywords:  amyotrophic lateral sclerosis (ALS); hydroxymethylglutaryl-CoA reductase inhibitors; motor neuron disease; statins; survival
    DOI:  https://doi.org/10.3389/fneur.2026.1753992
  6. Neurobiol Dis. 2026 Apr 13. pii: S0969-9961(26)00141-5. [Epub ahead of print]224 107396
    Elucidation of the influence of the CaV2.2 calcium channel on ALS disease progression in the SOD1*G93A mouse model.
    Katharina Wintz, Paul Luca Lechtape, Jannes Klenzendorf, Sarah Schemmert, Andrew J Dingley, Antje Willuweit, Janine Kutzsche.
      Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal neurodegenerative disease affecting upper and lower motor neurons in the central nervous system. Drugs like riluzole, edaravone, and tofersen treat disease symptoms or are designed for a specific pathological mutation (e.g., SOD1), but they cannot prevent or halt the disease. For this reason, the search for new therapeutic strategies continues. The voltage-gated calcium channel CaV2.2 might be a novel target in ALS treatment as the channel was shown to be overexpressed in murine SOD1*G93A cortical neurons, resulting in higher mortality. Further, murine SOD1*G93A motor neurons showed increased calcium currents mainly by an increased expression of the CaV2.2 channel. In addition, inhibition of the channel was hypothesized as mode of action for the all-d-enantiomeric peptide RD2RD2, a novel drug candidate for the treatment of ALS, which already demonstrated its efficacy in SOD1*G93A mice. To investigate the influence of the CaV2.2 channel on the progression of disease symptoms in the SOD1*G93A mouse model, a new double-transgenic line was created, combining the ALS phenotype with a knockout of the CaV2.2 channel. The study showed that the CaV2.2 knockout on the SOD1*G93A background led to reduced SHIRPA and splay scores, and a delayed disease onset. Additionally, differences were detected between wildtype and single-transgenic CaV2.2 knockout mice. However, survival was not affected. Post mortem analysis of human tissue found more CaV2.2 in ALS cases in comparison to healthy control subjects confirming involvement of the channel in human ALS. These results indicate that the CaV2.2 calcium channel may play an influential role in early disease progression of ALS.
    Keywords:  Amyotrophic lateral sclerosis; Behavior; Ca(V)2.2; Double-transgenic mice; Motor coordination; SOD1*G93A
    DOI:  https://doi.org/10.1016/j.nbd.2026.107396
  7. iScience. 2026 Mar 20. 29(3): 114988
    CAR Treg therapies for neurodegenerative diseases.
    Daniel N Stein, Howard E Gendelman.
      Regulatory T cells (Tregs) promote immune tolerance by recognizing non-foreign self-antigens. Consequently, Tregs suppress chronic immune responses and prevent autoimmunity. Chimeric antigen receptor Tregs (CAR Tregs) enhance Treg responses by genetic modification for cell-specific targeting. This can lead to effective treatments for autoimmune diseases, transplant rejection, and graft-versus-host disease. An extension of CAR Tregs involves their potential ability to regulate immune responses to misfolded and aggregated proteins, which drive neurodegenerative diseases. These protein aggregates can trigger immune responses that lead to neural injury. Early preclinical and translational strategies suggest CAR Treg therapies can treat Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. In each case, a Treg-based approach transforms a neurotoxic, inflammatory environment through neurotrophic responses. By doing so, CAR Tregs may restore brain balance and slow disease progression. This review highlights ongoing efforts to develop CAR Treg strategies as potential therapies for neurodegenerative disorders.
    Keywords:  Adaptive immunity; Chimeric antigen receptor; Neural homeostasis; Regulatory t cells
    DOI:  https://doi.org/10.1016/j.isci.2026.114988
  8. bioRxiv. 2026 Apr 11. pii: 2026.04.08.717296. [Epub ahead of print]
    A region-delineated snRNA-seq atlas of mouse spinal cord across lifespan resolves the interaction of normative aging programs with SOD1-G93A ALS.
    Michael Edison Pauli Ramos, Brijesh Kumar Singh, Oksana Shelest, Ian Tindel, Benisa Zogu, Ashley Dawson, Pranav Mathkar, Shaughn Bell, Ritchie Ho.
      Aging is the strongest risk factor for amyotrophic lateral sclerosis (ALS), yet how normative aging programs intersect with disease mechanisms remain unclear. Here we generated a lifespan-resolved, cell type- and region-specific single-nucleus RNA-sequencing atlas of the mouse spinal cord spanning embryonic development through advanced age in WT mice and end-stage disease in the SOD1-G93A ALS model. This resource enabled systematic comparison of physiological aging trajectories with disease-associated transcriptional changes across spinal cord cell types and rostrocaudal regions. We found that SOD1-G93A transcript and protein states differed markedly across spinal regions during disease onset and progression, and these molecular patterns paralleled the relative resilience of cervical regions and the heightened vulnerability of lumbar regions to degeneration in this transgenic mouse model. Prior to disease onset, we identified reduced ubiquitin expression that primed region-specific disruption of proteostasis in the SOD1-G93A spinal cord. Despite these disease-associated changes, aging-related transcriptional programs were largely preserved across most cell types, arguing against a global acceleration of aging in ALS. Instead, microglia emerged as a key exception, exhibiting accelerated and rewired aging- and disease-associated gene expression modules regulated by MITF and NRF2. Together, these findings provide an anatomically, cellularly, and temporally resolved framework for understanding how aging programs interact with disease-specific pathways to shape regional dysfunction and neurodegeneration in ALS.
    DOI:  https://doi.org/10.64898/2026.04.08.717296
  9. Clin Neurophysiol. 2026 Apr 09. pii: S1388-2457(26)00384-6. [Epub ahead of print]187 2111885
    Beyond motor output: disrupted kinesthesia reveals hidden sensory-cognitive dysfunction in amyotrophic lateral sclerosis.
    Raffaele Dubbioso.
      
    DOI:  https://doi.org/10.1016/j.clinph.2026.2111885
  10. Neural Regen Res. 2026 Apr 14.
    Mechanisms underlying neuroimmune networks as central regulators in combating neurodegenerative diseases.
    Xiangqi Hu, Mengfan Yao, Fenglan Xu, Huajun Wang, Ming Lu, Chen Qiao.
      Neuroimmune dysregulation is increasingly recognized as a key driver in the pathogenesis of neurodegenerative diseases. In addition to local glial responses within the central nervous system, neuroimmune dysregulation also involves peripheral immune activities and inter-organ communication networks. As previous studies have primarily concentrated on individual peripheral organs or specific immune cell types, the broader systemic immune network remains insufficiently investigated. To delay the onset and progression of neurodegenerative diseases, this review evaluates the latest therapeutic strategies and proposes feasible directions for the rational design of optimal immunomodulatory approaches. By focusing on central nervous system-intrinsic regulatory mechanisms, we delineate how microglia adopt context-dependent phenotypes and further elucidate the dynamic regulatory roles of astrocytes in maintaining blood-brain barrier integrity and synaptic homeostasis. Based on these insights, we propose a feasible direction for achieving a functional balance between neuroprotective phagocytosis and the regulation of chronic neuroinflammation. Furthermore, recent evidence indicates that peripheral immune populations, together with the central nervous system, also play a critical role in the therapeutic regulation of neurodegenerative diseases. As key components of peripheral immune populations, specific T-cell subsets can exert neuroprotective or neurotoxic effects, while B cells and macrophages also make notable contributions through antibody-independent mechanisms and metabolic reprogramming. This review outlines systemic pathways that connect peripheral organs to the brain, demonstrating how gut-derived metabolites, pulmonary immune responses, and renal-hepatic clearance collectively shape the immune regulation of the central nervous system. To achieve cell-specific modulation through neuroimmune pathways, this review further investigates glia-targeted therapeutic strategies, particularly in the areas of small molecules, biologics, and nanocarrier-based platforms. Meanwhile, this review also summarizes the current progress and limitations in neuroimmune-targeted drug development and offers valuable guidance for advancing future drug design. In summary, by integrating the analyses of single cells and multi-omics and utilizing organoid-based modeling, this review highlights the vital transition from broad immunosuppression to precision immunoregulation and proposes a novel regulatory framework spanning from the central to peripheral systems. It further offers targeted and feasible recommendations to advance neuroimmunology from theoretical exploration toward practical therapeutics. However, the implementation of these strategies still faces challenges from the temporal dynamics of immune activation, which could be potentially resolved by the enhancement of human glial cell-based biomimetic models and the improvement of stage-specific biomarkers.
    Keywords:  astrocyte; blood-brain barrier; central nervous system; immunotherapy; microglia; neurodegenerative diseases; neuroimmune; neuroinflammation; neuroprotection; peripheral immunity
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01276
  11. Front Neurosci. 2026 ;20 1806532
    Pharmacological interventions targeting the gut-brain axis in neurological disorders: mechanisms and translational applications.
    Xu Li, Wenke Zhou, Shuran Yang, Xiangkai Huang, Kuihong Zheng.
      The microbiota-gut-brain axis represents a complex bidirectional communication network linking the gastrointestinal system and the central nervous system and has been increasingly recognized as a key contributor to neurological and psychiatric disorders. Growing evidence indicates that alterations in gut microbiota composition and function can influence brain development and function through neural, immune, endocrine, and metabolic pathways, thereby modulating neuroinflammation, neurotransmission, and blood-brain barrier integrity. Dysregulation of this axis has been implicated in a range of conditions, including Parkinson's disease, Alzheimer's disease, multiple sclerosis, autism spectrum disorder, depression, anxiety, and stroke. Recent pharmacological advances have identified the microbiota-gut-brain axis as a promising therapeutic target. Current strategies focus on modulating shared pathophysiological mechanisms rather than disease-specific endpoints and include microbiota-directed interventions, immune-inflammatory modulators, neurotransmitter-targeting agents, and approaches aimed at restoring intestinal and blood-brain barrier function. In this review, we summarize the core mechanisms underlying microbiota-gut-brain axis dysfunction and organize existing pharmacological strategies according to their primary targets. By integrating evidence across multiple disorders, we provide a mechanism-oriented framework to support future drug development and precision therapeutic approaches for brain disorders.
    Keywords:  gut–brain axis; interventions; neurodegenerative diseases; pharmacological; precision medicine; therapies
    DOI:  https://doi.org/10.3389/fnins.2026.1806532
  12. Aging Dis. 2026 Apr 02.
    MAMs as a promising therapeutic strategy for age-related neurodegenerative diseases.
    Giacoma Galizzi.
      Aging is a natural process leading to the slow and progressive deterioration of numerous physiological functions. It is the main risk factor for several neurodegenerative diseases. Mitochondria-associated membranes (MAMs) or mitochondria-ER contacts (MERCs) are essential and dynamic sites of contact between mitochondria and the endoplasmic reticulum (ER) and are involved in numerous cellular processes, such as calcium (Ca2+) homeostasis, reactive oxygen species (ROS) production, autophagy, inflammation, mitochondrial dynamics, apoptosis, lipid biosynthesis, and trafficking. As a result, they play a significant role in maintaining cellular functionality regulating metabolism and ensuring proper stress responses. Recently, MAMs have been widely investigated to understand their critical role in cell physiology as well as in different pathological conditions. Increasing evidence indicates that alterations in ER-mitochondria communication contribute to aging and the development of age-related diseases. However, the cellular mechanisms underlying this link remain unclear. Understanding how these interactions change with age could provide further insights into the aging process and the mechanisms underlying age-related diseases, suggesting potential new therapeutic strategies. This review summarizes the current knowledge on MAM biology, focusing on their role in the pathogenesis of age-related brain disorders. Their therapeutic potential in limiting the progression of some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, and slowing the physiological aging process are also explored.
    DOI:  https://doi.org/10.14336/AD.2025.1342
  13. Int J Mol Sci. 2026 Apr 03. pii: 3260. [Epub ahead of print]27(7):
    Targeting Non-Coding RNAs as a Potential Therapeutic and Delivery Strategy Against Neurodegenerative Diseases.
    Anastasia Bougea.
      Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), represent a growing global health challenge characterized by progressive neuronal loss and a lack of definitive disease-modifying treatments. This review explores the emerging potential of targeting non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, to modulate pathogenic molecular pathways and address the underlying molecular origins of neurodegeneration. We evaluate the integration of advanced computational techniques for RNA structure prediction and gene regulatory network analysis, alongside chemical engineering strategies-such as Locked Nucleic Acids (LNAs) and phosphorothioate modifications-aimed at enhancing the stability and specificity of RNA-based molecules. Furthermore, we analyze cutting-edge delivery and editing technologies, including nanotechnology-driven solutions for precise neuronal targeting and the CRISPR/Cas13 system for direct ncRNA manipulation.The findings indicate that while challenges in delivery efficiency and long-term efficacy persist, the synergy of chemical engineering and computational modeling significantly improves the therapeutic profile of ncRNAs, with exosomal pathways offering a novel route for intercellular signaling modulation and biomarker discovery. Therapeutic interventions directed at specific clinical targets, such as miR-34a and BACE1-AS, demonstrate the capacity to influence protein aggregation and neuroinflammatory cascades. Although ncRNA-based therapies are currently in nascent stages, ongoing technological advancements in RNA editing and nanotechnology offer a transformative framework that could redefine the future of ND treatment and successfully halt disease progression rather than merely managing symptoms.
    Keywords:  CRISPR/Cas13; RNA therapeutics; blood–brain barrier; exosomes; gene regulation; nanotechnology; ncRNA; neurodegenerative diseases; non-coding RNAs; precision medicine
    DOI:  https://doi.org/10.3390/ijms27073260
  14. Sci Rep. 2026 Apr 14.
    Speech-based digital endpoints track ALS progression and align with standard clinical outcomes: evidence from the VRG50635 trial.
    Michael Neumann, Hardik Kothare, Meredith Bartlett, Oliver Roesler, Christiane Suendermann-Oeft, Abhishek Hosamath, Lakshmi Arbatti, David Pautler, David Suendermann-Oeft, Diego Cadavid, Robert H Scannevin, Ines Hoffmann, Anil Tarachandani, Tara Haley, Shane Raines, Philip Van Damme, Pentti Tienari, Eino Solje, Manu Jokela, Angela Genge, Colleen O'Connell, Ruben P A van Eijk, Leonard H van den Berg, Vikram Ramanarayanan.
      We report on the utility of speech-based digital endpoints measured during a Phase 1b study of VRG50635 in Amyotrophic Lateral Sclerosis (ALS). Fifty-four participants with ALS were enrolled and participated in an 8-week pretreatment run-in, followed by three 8-week dosing periods and an 8-week follow-up. They completed a speech assessment every two weeks in the clinic or at home. We observed moderate to high correlations between digital measures of speech timing and articulatory motor function, and the ALS Functional Rating Scale-Revised, slow vital capacity and plasma neurofilament light chain. Furthermore, speech measures can show functional decline before the ALSFRS-R does, while also capturing differences between participants with bulbar symptoms and those without. The results support the feasibility and utility of digital speech endpoints to study disease impact in ALS clinical trials.
    DOI:  https://doi.org/10.1038/s41598-026-48100-6
  15. Brain Res Bull. 2026 Apr 15. pii: S0361-9230(26)00176-0. [Epub ahead of print]239 111890
    The neuroprotective effect of guanabenz combined with α-lipoic acid in the hSOD1-G93A amyotrophic lateral sclerosis model.
    Wenmo Zhang, Dongmei Zhang, Ling Han, Di Wang, Di Huo, Xingli Tan, Xiaoli Su, Ming Wang, Jing Xu, Jiling Cheng, Honglin Feng.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, and although its pathogenesis is not yet clear, the multifactorial mechanisms that affect motor neuron death are intertwined, exacerbating the disease. Here, we explore the effectiveness and mechanism of a combination medication that combines guanabenz with α-lipoic acid in an in vitro as well as in vivo model of ALS. In this research, we initially determined the independent action targets and synergistic action targets of the two drugs through network pharmacology and molecular docking. Subsequently, we further investigated their specific action mechanisms in both in vivo and in vitro studies. In NSC34 cells transfected with hSOD1-G93A, we observed that the combined drugs could more effectively safeguard against cell damage and the production of reactive oxygen species (ROS) generated by mutant hSOD1, superior to monotherapy. This was achieved by upregulating the p-AKT/HO-1 pathway and synergistically suppressing the GRP78/CHOP pathway. Moreover, we found that combination drugs can effectively delay the decline in motor function of hSOD1-G93A transgenic mice by synergistically inhibiting GRP78/CHOP pathway. They can protect the motor neurons in the anterior horn of the spinal cord and suppress gliosis in hSOD1-G93A transgenic mice. In summary, our research indicates that the combination therapy of guanabenz and α-lipoic acid can serve as a viable treatment option for ALS.
    Keywords:  Amyotrophic lateral sclerosis; endoplasmic reticulum stress; neuroprotection; oxidative stress
    DOI:  https://doi.org/10.1016/j.brainresbull.2026.111890
  16. J Neurol. 2026 Apr 11. pii: 267. [Epub ahead of print]273(5):
    Weight maintenance following enteral nutrition is associated with prolonged survival in amyotrophic lateral sclerosis.
    Chiharu Matsuda, Yuki Nakayama, Michiko Haraguchi, Ryo Morishima, Yumi Itagaki, Kota Bokuda, Kentaro Hayashi, Kazushi Takahashi, Toshio Shimizu.
       OBJECTIVE: To investigate the association between energy intake at the initiation of enteral nutrition (EN), subsequent changes in body mass index (BMI), and survival in patients with amyotrophic lateral sclerosis (ALS).
    METHODS: This retrospective study included 121 patients with ALS who received EN. Annual BMI decline rates (∆BMI, kg/m2/year) were calculated for three periods: from symptom onset to diagnosis (T1-T2), from diagnosis to EN initiation (T2-T3), and from EN initiation to post-EN assessment (T3-T4). Energy intake per weight (E/W, kcal/kg/day) at EN initiation was also assessed. Survival after EN initiation was analyzed using Kaplan-Meier methods and Cox proportional hazards models.
    RESULTS: Post-EN BMI decline (∆BMIT3-T4) showed a significant negative correlation with E/W at T3 (p < 0.001). Patients with lower post-EN BMI decline (∆BMI < 0.8 kg/m2/year) had significantly longer survival after EN initiation than those with greater BMI decline (p < 0.001). Multivariate Cox analysis identified ∆BMIT3-T4 and pre-EN respiratory decline as independent predictors of post-EN survival. Subgroup analyses demonstrated that patients who maintained body weight after EN had better survival irrespective of energy intake at EN initiation.
    CONCLUSION: Weight maintenance following EN was associated with prolonged survival in ALS, whereas energy intake at EN initiation alone was not. These findings suggest that the survival benefit of nutritional intervention may be mediated through stabilization of body weight rather than caloric intake per se.
    Keywords:  Amyotrophic lateral sclerosis; Body mass index; Energy intake; Enteral nutrition; Survival
    DOI:  https://doi.org/10.1007/s00415-026-13776-3
  17. Dan Med J. 2026 Mar 19. pii: A09250733. [Epub ahead of print]73(4):
    Outpatient versus inpatient initiation of home mechanical ventilation in patients with amyotrophic lateral sclerosis - a protocol for a randomised trial.
    Janne Bøgh Stokholm, Simone Henrietta Lisa Küchen, Kirsten Møller, Mona Ring Gätke, Kirsten Svenstrup, Anne Kathrine Staehr-Rye.
       INTRODUCTION: In-home non-invasive ventilation (NIV) is associated with prolonged life and improved quality of life in patients with hypoventilation due to amyotrophic lateral sclerosis (ALS). The initiation of NIV is scheduled for a 1-2-night hospital stay. Telemedicine enables remote monitoring and adjustment of respiratory treatment. These possibilities should be examined to improve patients' experiences and adherence to treatment while freeing up resources in the healthcare system. We hypothesise that outpatient initiation of NIV combined with close telemonitoring in patients with ALS is non-inferior to standard initiation of NIV in adherence to treatment.
    METHODS: This is a randomised, controlled, non-inferiority study. A total of 46 patients with ALS scheduled for initiation of NIV are randomised to start NIV either as an outpatient combined with close telemonitoring or during hospitalisation for 1-2 nights. The primary outcome is NIV adherence after three months, measured as minutes per day for the past seven days. Secondary outcomes are patient satisfaction with NIV treatment and its initiation after three months, assessed on a 1-5 rating scale.
    CONCLUSIONS: The study is the first randomised, controlled study assessing the combination of outpatient initiation of NIV and close telemedical follow-up in patients with a progressive neuromuscular disease. The results may be applicable to other patient populations initiating NIV, e.g., patients with obesity hypoventilation syndrome.
    FUNDING: The study was supported by grants from ALS-fonden and Muskelsvindfonden.
    TRIAL REGISTRATION: NCT05829330.
    DOI:  https://doi.org/10.61409/A09250733
  18. Front Neurol. 2026 ;17 1751139
    MRI abnormal patterns of lumbar paraspinal muscles in patients with amyotrophic lateral sclerosis and lumbosacral radiculopathy: a comparative study.
    Yuting Ren, Xu Han, Kang Zhang, Songtao Niu, Bin Chen, Xingao Wang, Fan Jian, Hua Pan, Zaiqiang Zhang, Xin Chen.
       Background: Recent evidence highlights the potential predictive value of paraspinal muscle degeneration in amyotrophic lateral sclerosis (ALS). However, the magnetic resonance imaging (MRI) characteristics of degeneration in lumbar paraspinal muscles in ALS and lumbosacral radiculopathy (LR) remain unclear.
    Methods: Comparison of fatty infiltration (FI) and relative cross-sectional area (rCSA) of the paraspinal muscles was conducted between 38 ALS patients and 32 LR patients.
    Results: The mean rCSA of the multifidus (MF), erector spinae (ES), and psoas major (PM) muscles was lower on the symptomatic onset side compared to the contralateral side at the L3-L5 segments in patients with ALS. On the symptomatic onset side, the FI of the ES (L1-L4 segments), MF (L4 segment), and PM muscles (L1, L2, and L4 segments) was significantly higher in ALS patients who had pathological spontaneous activity (PSA) than in those without PSA. At the L3-L5 segments on the symptomatic onset side, the mean rCSA of the MF, ES, and PM muscles was significantly higher in LR patients compared to ALS patients (p < 0.01). Similar differences in the rCSA of the MF, ES, and PM muscles were observed between lower limb-onset ALS patients and LR patients (p < 0.05). In addition, mild associations were observed between declines in the ALS functional rating scale (ALSFRS)-lower score and decreases in the rCSA of MF and PM muscles, as well as increased FI of the MF and ES muscles.
    Conclusion: The decrease in the rCSA of the paraspinal muscles on the symptomatic onset side suggests progressive involvement of muscle fibers in ALS patients. The presence of PSA in the paraspinal muscles appears to be more valuable and sensitive for evaluating fatty substitution than muscle atrophy in ALS. MRI parameters of the paraspinal muscles may be useful for monitoring disease progression in ALS and distinguishing ALS, especially lower limb-onset cases, from pauci-symptomatic LR.
    Keywords:  amyotrophic lateral sclerosis; fatty infiltration; lumbosacral radiculopathy; magnetic resonance imaging; paraspinal muscles; relative cross-sectional area
    DOI:  https://doi.org/10.3389/fneur.2026.1751139
  19. Autophagy. 2026 Apr 12.
    Discovery of a novel TFEB activator targeting lysosomal dysfunction in amyotrophic lateral sclerosis using artificial intelligence-based virtual screening.
    Ang Li, Xianglu Xiao, Dajiang Qin, Huanxing Su.
      Lysosomal dysfunction is a defining feature of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), yet effective pharmacological strategies to restore lysosomal homeostasis remain limited. Transcription factor EB (TFEB), a master transcriptional regulator of lysosomal biogenesis, has emerged as an attractive therapeutic target. In our recent study published in Pharmacological Research, we established a robust artificial intelligence (AI) - driven virtual screening pipeline and identified isoginkgetin (ISO) as a potent TFEB activator that effectively promotes lysosomal biogenesis and enhances lysosomal function. Importantly, ISO exhibits potent neuroprotective effects against motor neuron degeneration in ALS models. Using this AI-driven strategy, we identified a previously unrecognized neuroprotective mechanism by which ISO protects motor neurons through TFEB-dependent restoration of lysosomal function, validating lysosomal function as a promising therapeutic target for ALS. Collectively, this work establishes that AI-powered screening to identify mTORC1-independent TFEB agonists is a valuable paradigm for the discovery and development of therapeutic agents against ALS and other neurodegenerative diseases.
    Keywords:  Amyotrophic lateral sclerosis; Isoginkgetin; Lysosome; artificial intelligence; transcription factor EB
    DOI:  https://doi.org/10.1080/15548627.2026.2659295
  20. HGG Adv. 2026 Apr 10. pii: S2666-2477(26)00054-0. [Epub ahead of print] 100614
    Genetic contributions to mitochondrial dysfunction in amyotrophic lateral sclerosis etiology.
    Nikki D Russell, Jonathan M Downie, Mark B Bromberg, Stefan M Pulst, Lynn B Jorde.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with multiple genetic causes. Given the strong evidence of mitochondrial dysfunction in ALS, this study aimed to identify genetic contributors to ALS by focusing on genes involved in mitochondrial function. Whole-genome and exome sequencing data from 1,034 ALS cases were analyzed using two distinct computational tools, which ranked candidate genes based on functional relevance to ALS. POLG, the sole mitochondrial DNA polymerase, emerged as a top candidate gene. RNA-seq analysis revealed that among genes upregulated in samples with a POLG variant, there was an enrichment for mitochondrial pathways such as translation, localization, and mitophagy. It also revealed variants in POLG and SOD1, a well-known ALS gene, to be the most enriched in samples with expression profiles of mitochondrial-related genes that differed most from those of unaffected controls. POLG variant carriers also exhibited an increased burden of mitochondrial genome variants, a pattern shared by carriers of variants in other genes involved in mitochondrial DNA maintenance. Additionally, POLG variant carriers had elevated mitochondrial DNA copy number (mtDNA-CN), similar to carriers of variants in mitophagy-related genes, suggesting impaired mitophagy. Together, these findings implicate POLG as an ALS-associated gene and link mitochondrial DNA maintenance defects, altered expression of mitochondrial-related pathways, and impaired mitophagy to ALS etiology.
    DOI:  https://doi.org/10.1016/j.xhgg.2026.100614
  21. Front Cell Dev Biol. 2026 ;14 1755814
    Dynamic changes in excitability and viability of sporadic and SOD1-related amyotrophic lateral sclerosis iPSC-derived motor neurons.
    Ming Qi, Nan Hu, Jianfeng Ding, Jingwen Niu, Bo Long, Mingsheng Liu.
       Objective: To explore the dynamic changes in excitability and viability of induced pluripotent stem cells (iPSC)-derived motor neurons from sporadic amyotrophic lateral sclerosis (ALS) and compare them with SOD1-related ALS patients and healthy control.
    Methods: Peripheral blood samples were collected from ALS patients and healthy controls (HC) to establish the iPSC-derived motor neurons (MNs). Whole-cell patch-clamp recordings at different culture stages was made using an Axopatch 700B amplifier in combination with pClamp 11 software (Molecular Devices). The frequency of action potentials (APs) was recorded. Additionally, Terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) Nick-End Labeling (TUNEL) was used to assess the apoptosis of MNs.
    Results: ALS patient-derived MNs exhibited significantly higher firing rates compared to HCs at both 4-7 weeks (p = 0.004) and 7-9 weeks (p = 0.009). Further analysis revealed that SOD1-derived MNs showed significantly higher firing frequencies than sALS (p = 0.009) and HCs (p < 0.001) in 4-7 weeks. In 7-9 weeks, it remained significant between SOD1 and HC-derived MNs (p = 0.015), but became insignificant between SOD1 and sALS (p = 0.855). The apoptotic rate of sALS (Day 30: 61.37% ± 9.63%; Day 60: 78.41% ± 6.63%) and SOD1 (Day 30: 73.69% ± 8.81%; Day 60: 60.37% ± 11.53%) -derived MNs was significantly higher than those of HCs at both Day 30 (30.72% ± 7.57%) and Day 60 (50.85% ± 19.36%) (p < 0.001).
    Conclusion: MNs derived from both patients with mutant SOD1 and sporadic ALS exhibited increased excitability compared to HCs. The increased excitability of MNs derived from ALS patients with mutant SOD1 occurred earlier, and over time, became consistent with the excitability observed in MNs derived from sporadic ALS. The apoptosis rates of MNs showed similar trends. iPSC-derived MNs from both sporadic and mutant ALS may serve as useful cell models for ALS in future studies.
    Keywords:  ALS; IPSC; apoptosis; hyperexcitability; motor neuron (MN)
    DOI:  https://doi.org/10.3389/fcell.2026.1755814
  22. Neurotherapeutics. 2026 Apr 10. pii: S1878-7479(26)00074-7. [Epub ahead of print]23(3): e00904
    Nose-to-brain delivery of a SOD1-stabilizing small molecule ameliorates pathology in an ALS mouse model.
    Ranjithkumar Dhandapani, Shamchal Bakavayev, Anna Armoza, Marina Bersudsky, Arina Shlifer, Galit Yehezkel, Alexandra Tsitrina, Zeev Barak, Amnon C Sintov, Stanislav Engel.
      Exposure of a pathogenic β6/β7 loop neo-epitope has been proposed to contribute to the pathogenesis of misfolded Cu/Zn superoxide dismutase (SOD1) in amyotrophic lateral sclerosis (ALS) by mediating early events in its noxious structural transformation and prion-like activity. Antibody-mediated blockade of this epitope was shown to ameliorate disease phenotype in an ALS animal model. Here, as an alternative strategy, we sought to block this epitope using a small molecule designed to occupy the inter-subunit cavity framed by the two β6/β7 loops. Using a structure-based virtual screen targeting this cavity, we identified a small molecule, N-[3-(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)phenyl]-4-sulfamoylbenzamide (C7), that preferentially bound the native-like conformation of SOD1, reduced β6/β7 loop epitope accessibility, and inhibited irreversible apo-SOD1 misfolding in vitro. Delivered to presymptomatic hSOD1G93A mice via a nanoparticle-based nose-to-brain delivery system, C7 significantly delayed the onset of motor abnormalities and modestly extended survival. At disease onset, spinal cord analysis revealed reduced misfolded SOD1 inclusions and attenuated astro- and microgliosis. Analysis of C7 concentrations in combined brain and spinal cord tissue indicated rapid but saturable nose-to-CNS uptake and slow clearance. Our findings demonstrate that targeting the surface cavity shaped by the β6/β7 loops of SOD1 with a reversibly-binding small molecule can ameliorate ALS-like disease in vivo, potentially by counteracting early misfolding events and/or limiting prion-like propagation of molecular pathology. However, saturable nose-to-CNS uptake of C7 restricts CNS exposure and likely constrains therapeutic efficacy, underscoring the need to define the rate-limiting pharmacokinetic step and to optimize the nanoparticle formulation and/or physicochemical properties of the C7 scaffold.
    Keywords:  ALS; Misfolding; Nose-to-brain CNS delivery; SOD1; Small-molecule compounds; Virtual screen
    DOI:  https://doi.org/10.1016/j.neurot.2026.e00904
  23. Neural Regen Res. 2026 Apr 14.
    Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases.
    Valentina Tedeschi, Raffaella Ciancio, Silvia Piccirillo, Alessandra Preziuso, Tiziano Serfilippi, Valentina Terenzi, Simona Magi, Vincenzo Lariccia, Pasqualina Castaldo, Antonio Vinciguerra, Ilaria Piccialli, Lorella Maria Teresa Canzoniero, Anna Pannaccione, Agnese Secondo.
      Several lines of evidence suggest that targeting dysfunctional calcium (Ca2+)-storing organelles and their defective connections may represent a promising therapeutic strategy counteracting neurodegeneration. Dysfunction in these compartments converges to promote oxidative and endoplasmic reticulum stress, energy failure, autophagy blockade or hyperactivation, and progressive neurodegeneration. Within the intracellular scenario, several dysfunctional organelles have been characterized in terms of their capability to hijack Ca2+ signaling during neurodegeneration to deadly impact on neuronal tasks in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, brain ischemia, and neonatal hypoxic injury. This review has focused on the endoplasmic reticulum, mitochondria, and lysosomes, as well as their functional interconnection able to maintain the physiological processes such as lysosomal-dependent autophagy and function, lipid trafficking, and protein quality control. Clinically, looking ahead from the already existing therapies, drugs that enhance mitochondrial Ca2+ efflux or modulate mitochondrial Ca2+ uniporter regulation at mitochondria-associated membranes-endoplasmic reticulum sites represent innovative opportunities for next-generation strategies aimed at restoring mitochondrial homeostasis and protecting dopaminergic neurons in Parkinson's disease. Furthermore, functional stabilization of the lysosomal channel transient receptor potential mucolipin 1 by the lipid-based formulation of PI(3,5)P2 may extend the lifespan of amyotrophic lateral sclerosis mice by stimulating the nuclear translocation of the master regulator of autophagy activated by lysosomal Ca2+ release, namely transcription factor EB. Moreover, dysfunction of lysosomal-dependent autophagy can cause mutant huntingtin accumulation in Huntington's disease through the repression of transcription factor EB and lysophagy induction. Collectively, this growing focus may highlight a shift toward recognizing mitochondria, lysosomes, and endoplasmic reticulum, as well as their ionic machinery and interconnections, as a unifying strategy to maintain neuronal viability and mitigate the neurodegeneration progression in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, lysosomal storage diseases, brain ischemia, and neonatal hypoxic insult.
    Keywords:  ; autophagy; channels; endoplasmic reticulum; endoplasmic reticulum stress; lysosome; mitochondria; mitochondria-associated membranes; neurodegenerative diseases
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01754
  24. Sleep Med. 2026 Apr 12. pii: S1389-9457(26)00200-5. [Epub ahead of print]144 108961
    Sleep spindle alterations as a novel biomarker for phenotypic stratification in sporadic amyotrophic lateral sclerosis.
    Min Li, Meiqi Han, Xin Li, Ning Yu, Xinyi Zhang, Luqi Zhao, Qi Liu, Hu Liu, Jianping Wu, Zhongwen Han, Hui Dong, Yaling Liu.
       OBJECTIVE: To quantitatively evaluate sleep spindle alterations in sporadic amyotrophic lateral sclerosis (ALS) and explore their potential as biomarkers for diagnosis and phenotypic stratification.
    METHODS: In this cross-sectional study, overnight sleep electroencephalography was recorded in 97 sporadic ALS patients and 73 matched healthy controls. Sleep spindle parameters (amplitude, duration, density, frequency) were automatically analyzed at frontal leads. Multiple comparisons were controlled using the false discovery rate (FDR) approach. We used least absolute shrinkage and selection operator (LASSO) regression for diagnostic modeling and employed K-means clustering to define spindle-based subtypes. Bootstrap internal validation was performed to assess model optimism.
    RESULTS: After FDR correction, ALS patients showed significant spindle abnormalities predominantly in the bipolar FP12 derivation, including reduced slow spindle density (p-FDR = 0.007), reduced overall spindle density (p-FDR = 0.007), and shortened slow spindle duration (p-FDR = 0.017). A diagnostic model incorporating Epworth Sleepiness Scale score, wake after sleep onset, sleep efficiency, FP12 slow spindle density, and education years showed promising discriminative ability (apparent AUC = 0.931; optimism-corrected AUC = 0.923). Unsupervised clustering consistently revealed two distinct spindle phenotypes. The "spindle-deficient" phenotype, characterized by poorer spindle integrity, was independently associated with lower ALSFRS-R scores (OR 1.101, 95% CI 1.024-1.202, p = 0.017), lower percentage of predicted forced vital capacity (OR 1.035, 95% CI 1.010-1.065, p = 0.011), and absence of drinking history (OR 3.03, 95% CI 1.02-9.46, p = 0.049).
    CONCLUSIONS: Sleep spindle alterations may represent a core electrophysiological feature of ALS, potentially reflecting thalamocortical dysfunction. These exploratory findings suggest that spindle parameters could serve as candidate biomarkers for disease stratification, though validation in independent longitudinal cohorts is needed before clinical application.
    Keywords:  Amyotrophic lateral sclerosis; Biomarker; Phenotype; Portable sleep electroencephalography monitoring device; Sleep spindle
    DOI:  https://doi.org/10.1016/j.sleep.2026.108961
  25. Protein Sci. 2026 May;35(5): e70565
    An ALS-associated mutation in the C-terminal α-helix of TDP-43 uncouples condensate formation and amyloid assembly.
    Emily J Byrd, Joel A Crossley, Chalmers C C Chau, Paolo Actis, Antonio N Calabrese.
      TAR DNA-binding protein 43 (TDP-43) plays a critical role in RNA metabolism and is incorporated into biomolecular condensates called stress granules. In amyotrophic lateral sclerosis (ALS) and several other neurodegenerative disorders, TDP-43 undergoes aberrant phase transitions, forming insoluble amyloid aggregates, including fibrils composed of solely its intrinsically disordered C-terminal domain (CTD). Despite its central role in disease, the conformational dynamics of the CTD remain poorly understood due to its heterogeneous and transient conformational landscape. Here, we employ native ion mobility-mass spectrometry (IM-MS) using nanopipette sub-micron nano electrospray ionization (nanoESI) emitters to characterize the conformational landscape of wild-type and ALS-associated TDP-43 CTD variants (Q331K and R361S) under different solution conditions. Our data suggest that mutations and salt concentration modulate the CTD's conformations. Combined with thioflavin T fluorescence, light scattering, and microscopy, we reveal that these conformational shifts correlate with altered amyloid assembly kinetics and propensity to form condensates. Notably, the Q331K variant, which has a mutation in the transient α-helical region in the CTD, has reduced propensity to form biomolecular condensates but can undergo amyloid assembly in the absence of condensate formation, suggesting that sequence alterations in this α-helical region can tune the molecular mechanism of amyloid assembly. This study demonstrates the power of IM-MS in probing disordered proteins and reveals mechanistic insights into how disease-associated mutations differentially tune TDP-43 CTD amyloid assembly mechanisms.
    Keywords:  Ion mobility–mass spectrometry; TDP‐43 C‐terminal domain; amyloid assembly; biomolecular condensates; intrinsically disordered proteins
    DOI:  https://doi.org/10.1002/pro.70565
  26. Neurol Neurochir Pol. 2026 Apr 14.
    Exploring the phenotypic spectrum of frontotemporal lobar degeneration.
    Jiya Patel, Samantha R Eisenberg-Godsey, Philip W Tipton.
      Frontotemporal lobar degeneration (FTLD) refers to a spectrum of neuropathology preferentially affecting the frontal and temporal lobes manifesting with progressive behavioral, language, and motor impairment. These clinical symptoms linked to FTLD are collectively referred to as frontotemporal spectrum disorders (FTSD) and include behavioral-variant frontotemporal dementia, nonfluent/agrammatic primary progressive aphasia, semantic variant primary progressive aphasia, right temporal variant frontotemporal dementia, corticobasal syndrome, progressive supranuclear palsy, and amyotrophic lateral sclerosis-frontotemporal spectrum disorders. While some patients with FTLD present with a single, well-defined syndrome, others exhibit features of multiple syndromes, and clinical phenotypes frequently evolve over time. Moreover, there is substantial phenotypic overlap between FTSD and other neurological disorders, contributing to frequent misdiagnosis and diagnostic delays. To address these challenges, we provide a practical, clinically oriented framework for the diagnosis of FTSD. We review common and nuanced clinical features, pertinent diagnostic testing, and the role of genetic testing in the context of current understanding of neuropathological correlates. Despite the absence of disease-modifying therapies, we also outline evidence-informed strategies for the symptomatic management of FTSD.
    Keywords:  amyotrophic lateral sclerosis; aphasia; dementia; frontotemporal lobar degeneration; frontotemporal spectrum disorders; genetics; parkinsonism
    DOI:  https://doi.org/10.5603/pjnns.109796
  27. Comput Biol Chem. 2026 Apr 14. pii: S1476-9271(26)00174-X. [Epub ahead of print]123 109049
    BrainShuttle-ESM: A Multi-Stage Transformer Architecture for Predicting Blood-Brain Barrier-Penetrating Short Peptides.
    Sathiyajith J N, Gopi Mohan C, Pratiti Bhadra.
       BACKGROUND: The blood-brain barrier (BBB) is a critical protective semi-permeable membrane that separates the bloodstream from brain tissue, preventing harmful substances from entering the central nervous system and maintaining brain homeostasis. However, this protective function also restricts the permeation of most therapeutic molecules, making drug delivery to the brain a major challenge. Among the strategies explored to overcome this limitation, blood-brain barrier-penetrating peptides (B3PPs) have emerged as a particularly promising class of molecules. These peptides, especially shorter ones (5-20 amino acids), can function as both delivery shuttles and therapeutic agents. Their small size, inherent neuroprotective properties, and amenability to chemical modification make them attractive candidates. Despite growing interest, current computational approaches have not been explicitly designed to predict short BBB-penetrating peptides.
    METHODS: To address this gap, we developed BrainShuttle-ESM, a fine-tuned ESM-2-based model specifically trained to predict BBB penetration of short peptides. Using a multi-stage fine-tuning strategy incorporating balanced positive peptides and structurally diverse negative examples, we trained the model to classify peptides based on their BBB-penetrating potential. Attention-map analysis was subsequently employed to facilitate interpretation of the model's predictions and to highlight physicochemical features that may contribute to its performance.
    RESULTS: The model demonstrated strong performance, achieving an AUC-ROC of 0.88±0.007 and an F1-score of 0.83±0.009. Attention-map analysis indicated that amphipathic residues consistently receive high attention weights, suggesting a potential role of amphipathicity in BBB permeability, consistent with prior experimental observations. The analysis also suggests that hydrophobicity and side-chain dihedral angles may be associated with membrane penetration. Additionally, we developed a user-friendly web server to allow researchers to screen peptide sequences for BBB-penetrating potential.
    CONCLUSION: BrainShuttle-ESM is an LLM-based computational model for identifying short BBB-penetrating peptides. Residue-level attention analysis suggested potential associations with amphipathicity and hydrophobicity. The study emphasizes the importance of dual-functional peptides that combine BBB penetration with additional therapeutic properties to support peptide-based drug development for neurological disorders, with BrainShuttle-ESM offering potential to accelerate this process.
    Keywords:  Attention-based interpretability; Blood–brain barrier penetration; ESM-2; Prediction model; Protein large language model; Short peptide
    DOI:  https://doi.org/10.1016/j.compbiolchem.2026.109049
  28. Molecules. 2026 Apr 07. pii: 1227. [Epub ahead of print]31(7):
    Anti-Neuroinflammatory Cannabinoid Acids as a New Therapeutic Approach for Multiple Sclerosis.
    Nitsan Sharon, Yvonne Ventura, Nirit Bernstein, Jonathan Gorelick, Shimon Ben-Shabat, Sigal Fleisher-Berkovich.
      Neuroinflammation is a hallmark of multiple sclerosis (MS). MS is marked by glial cell activation, autoreactive T cells, and the release of pro-inflammatory cytokines and free radicals. Current therapeutic strategies aim to modulate the immune response using disease-modifying therapies, to slow disease progression. The specific aims of this study were: (a) to investigate the effect of cannabinoid acids on the release of glial neuroinflammatory mediators, (b) to examine the effect of intraperitoneally administered cannabinoid acids on symptoms of MS, and (c) to evaluate their effects on microglial and astrocyte activation and CD4+ T cell infiltration into the spinal cords of MS mice. Exposure of BV2 microglia to cannabinoid acids attenuated lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase by 40-90% it also reduced the release of nitric oxide and interleukin-17A. Among the cannabinoid acids tested, cannabidiolic acid (CBDA) significantly increased tumor necrosis factor alpha (TNFα) secretion by up to 40% in LPS-stimulated BV2 cells. Intraperitoneal administration of CBDA also resulted in a twofold increase in TNFα secretion in splenocytes isolated from MS mice, compared to untreated MS controls. This study provides evidence that CBDA significantly reduces neurological scores, while both cannabinoid acids attenuate microgliosis, astrogliosis, and CD4+ T cell migration in lumbar spinal cord sections of MS mice. These compounds cross the blood-brain barrier (BBB) and act directly within the central nervous system. The consistent elevation of TNFα in the presence of CBDA across three experimental models suggests a distinctive immunomodulatory role for CBDA, with potential therapeutic implications in MS.
    Keywords:  cannabinoid acids; lipopolysaccharide; microglia; multiple sclerosis; neuroinflammation
    DOI:  https://doi.org/10.3390/molecules31071227
  29. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Apr 13. 1-11
    Development of a machine learning-based survival prediction model for ALS inclusive of the advanced-stage population.
    Pooled Resource Open-Access ALS Clinical Trials Consortium
       OBJECTIVE: Develop a machine learning-based model for survival prediction in ALS, including advanced-stage patients (≤50% predicted normal vital capacity [VC50]).
    METHODS: Training data from the PRO-ACT Database (n = 6896) was supplemented with advanced-stage ALS patients (n = 678), with model validation on distinct advanced-stage ALS patients (n = 403). Baseline patient characteristics, including slopes from symptom onset, were used to train a random forest model to identify parameters with the greatest relative importance (RI) for predicting survival outcomes. These parameters were used to train a gradient-boosting machine (GBM) model that generated patient-level survival predictions (log-hazard). Model discrimination and calibration were quantified by C-index and calibration-in-the-large plus calibration slope, respectively. Kaplan-Meier curves were generated, with patient stratification into tertiles based on the predicted survival risk score.
    RESULTS: Baseline characteristics with the highest RI for driving survival predictions included: VC% slope (20.2%); age (12.4%); VC% (9.9%); VC(L) (7.5%); ALSFRS-R (6.6%); and ALSFRS-R slope (5.1%). Model performance upon external validation was satisfactory for both discrimination (C-index, 0.709 [95% CI, 0.671-0.746]) and calibration (calibration-in-the-large, 0.083 [95% CI, -0.073-0.232]; calibration slope, 0.992 [95% CI, 0.789-1.198]). At 8-months from baseline, the model successfully stratified patients by survival prognosis, with low-, average-, and high-risk population tertiles having observed median survival probabilities of 85, 69, and 43%, respectively.
    CONCLUSIONS: This model accurately predicts survival prognosis in ALS, including patients with severely impaired respiratory function. This new understanding of patient-specific factors that drive survival prognostication will be invaluable for reducing patient heterogeneity in clinical trials evaluating novel therapeutic modalities in early- and advanced-stage ALS.
    Keywords:  Amyotrophic lateral sclerosis; gradient boosting machine model; respiratory insufficiency; survival; vital capacity
    DOI:  https://doi.org/10.1080/21678421.2026.2652322
  30. PLoS One. 2026 ;21(4): e0347135
    Dysregulated lactate metabolism synergizes with ALS genetic risk factors to accelerate motor decline.
    Shweta Tendulkar, Tong Wu, Amy Strickland, Amber R Hackett, Yurie Sato-Yamada, Xianrong Mao, Yo Sasaki, Jeffrey Milbrandt, A Joseph Bloom, Aaron DiAntonio.
      Neurons rely on glial 'lactate shuttling' for metabolic support, which declines with aging and in neurodegenerative disease. Full disruption of lactate shuttling in peripheral nerves causes progressive axon degeneration, but we were interested to understand how partial disruption, a scenario more relevant to aging and disease, contributes to neurodegeneration risk. Pyruvate and lactate are interconverted by lactate dehydrogenases (LDHA and LDHB) in both lactate producing and consuming cells. We therefore began by investigating Ldhb knockout mice (loss of LDHA, the dominant LDH in liver and muscle, caused embryonic lethality), and discovered that they develop progressive neuromuscular junction atrophy and functional decline without axon degeneration. Because even Ldhb+/- heterozygosity significantly affects motor behavior, we also wondered about a potential link to congenital disease and pursued this by identifying rare loss-of-function LDHB variants among ALS patients. Next, to better understand how LDHB loss leads to motor decline, we selectively deleted it in defined cell types. Schwann cell (SC)-specific deletion caused robust motor defects, whereas motor neuron-specific deletion has little effect. Reasoning that neuronal LDHB deficiency could model age-associated decline in lactate metabolism, we asked whether it would interact with ALS genetic risk. Indeed, motor-neuron LDHB deficiency synergizes with relatively mild ALS risk variants- TDP43Q331K and Sod1D83G knock-in alleles-to produce early motor neuropathy, indicating that LDHB loss enhances disease risk. These findings establish lactate metabolism as a modifier of motor system vulnerability and highlight it as a therapeutic target in peripheral as well as central neurodegeneration.
    DOI:  https://doi.org/10.1371/journal.pone.0347135
  31. Hum Cell. 2026 Apr 16. pii: 66. [Epub ahead of print]39(5):
    Pathogenesis and therapeutic strategies for neuropsychiatric lupus centered on innate immune activation.
    Wataru Nagata, Toshiaki Ishizuka.
      Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious central nervous system complication of systemic lupus erythematosus (SLE) that markedly reduces patient quality of life. Despite its clinical importance, the underlying mechanisms remain incompletely defined, and effective treatments are limited. In this review, we synthesize preclinical and clinical evidence that aberrant activation of innate immunity by self-nucleic acids and consequent overproduction of Type I interferons (IFN-I) constitute a central pathogenic axis in NPSLE. IFN-I and other inflammatory mediators promote disruption of the blood-brain barrier (BBB), enabling entry of autoantibodies, cytokines, and immune cells into the brain. These factors, together with damage-associated molecular patterns, activate microglia and astrocytes, driving sustained neuroinflammation that provokes synaptic loss, neurotransmitter dysregulation, excitotoxic neuronal injury, impaired neurogenesis, and mitochondrial dysfunction-mechanisms that underlie cognitive impairment, mood disorders, and other neuropsychiatric manifestations. We review therapeutic strategies targeting each step of this cascade, including blockade of IFN-I signaling (e.g., anifrolumab), inhibition of endosomal nucleic acid sensing (TLR antagonists), cytokine and JAK inhibition, modulation of microglial function (CSF1R inhibitors), and approaches to protect or restore BBB integrity (e.g., statins). Finally, we discuss biomarker-guided patient stratification and trial designs necessary to address NPSLE heterogeneity and accelerate the development of personalized therapies. By elucidating the cellular responses of the neurovascular unit to innate immune insults, this review provides a molecular framework for developing targeted therapies for NPSLE.
    Keywords:  Blood–brain barrier; Immunity; Innate; Interferon type I; Neuropsychiatry; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1007/s13577-026-01381-5
  32. Int J Mol Sci. 2026 Mar 27. pii: 3076. [Epub ahead of print]27(7):
    N-Acetylcysteine in Neurological Disorders: A Systematic Review of Clinical and Translational Evidence Across Seven Disorders.
    Robert Mîndreanu, Irina Camelia Chiș, Alexandra Sevastre-Berghian, Cezar Login, Adina Stan, Teodora Stan, Simona Clichici, Șoimița Suciu.
      N-acetylcysteine (NAC) is a glutathione precursor with established antioxidant and anti-inflammatory properties that has been investigated as a neuroprotective agent across multiple neurological conditions. This systematic review systematically mapped the clinical evidence for NAC across seven neurological disorders. PubMed and Cochrane Library were searched for studies published between 1 January 1995 and 31 December 2025. Twenty-three studies were included: traumatic brain injury (TBI, n = 6), Alzheimer's disease (AD, n = 5), Parkinson's disease (PD, n = 5), multiple sclerosis (n = 4), amyotrophic lateral sclerosis (n = 2), and migraine (n = 1); no eligible epilepsy studies were identified. The strongest evidence emerged for acute mild TBI, where early NAC administration significantly improved symptom resolution, and for PD, where combined intravenous/oral NAC improved dopamine transporter binding. In AD, nutraceutical formulations including NAC and other active compounds showed trends toward cognitive stabilization. Most included studies had a high or serious risk of bias, and only eight of 23 assessed oxidative stress biomarkers. NAC demonstrated a favorable safety profile across all conditions. Despite fragmented and heterogeneous evidence, the encouraging signals identified warrant large-scale randomized controlled trials with a standardized biomarker assessment.
    Keywords:  Alzheimer’s disease; N-acetylcysteine; Parkinson’s disease; amyotrophic lateral sclerosis; migraine; multiple sclerosis; oxidative stress; traumatic brain injury
    DOI:  https://doi.org/10.3390/ijms27073076
  33. J Neurochem. 2026 Apr;170(4): e70426
    Simultaneous Expression of Sigma-1 Receptor and Tetraspanins Highlights Pathways of Receptor Sorting Into Extracellular Vesicles.
    Edijs Vavers, Sergei Kopanchuk, Santa Veiksina, Jolanta Jonane, Chaitanya Mathur, Naila Nasirova, Getnet Midekessa, Ago Rinken.
      Sigma-1 receptor (Sig1R) is an endoplasmic reticulum (ER) chaperone protein involved in regulating ER function, cellular stress responses, and autophagy, and disturbed Sig1R function has been associated with neurodegenerative and neuropsychiatric disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. Although Sig1R has been implicated in secretory pathways and detected extracellularly, its direct presence in isolated extracellular vesicles (EVs) has not been clearly established. In this study, we aimed to confirm Sig1R in isolated EVs by co-expressing it alongside tetraspanin EV markers. Expression of fluorescently tagged Sig1R together with fluorescent protein-labeled tetraspanins CD9, CD63, and CD81 in both cells and isolated EVs was verified using live-cell imaging, emission spectrum measurements, and Western blotting. Efficient expression of these proteins in cells was achieved by using the MultiBacMam expression system and their presence in EVs was detected through advanced TIRF-based multi-well single-particle EV analysis. We observed significantly higher levels of Sig1R in CD63- and CD9-labeled EVs in comparison with CD81-labeled EVs. The obtained data suggest that Sig1R may be released into the extracellular space via exocytotic pathways linked to exosome secretion. The presence of Sig1R in exosomes underscores its potential as a biomarker in neurological disorders, emphasizing the need for further exploration of its diagnostic and other applications.
    Keywords:  MultiBacMam system; TIRF microscopy; exosomes; sigma‐1 receptor; tetraspanins
    DOI:  https://doi.org/10.1111/jnc.70426
  34. J Clin Invest. 2026 Apr 15. pii: e199850. [Epub ahead of print]136(8):
    Immune signaling and function in neurodegeneration.
    Yvonne L Latour, Dorian B McGavern.
      Neurodegenerative diseases arise from interactions among pathogenic proteins, immune responses, and diverse environmental or age-related stressors that disrupt CNS homeostasis. CNS resident microglia detect self-derived danger signals through pattern recognition receptors, and their activation can promote clearance of aberrant proteins, including amyloid-β, tau, α-synuclein, and TAR DNA-binding protein 43. However, microglial activation may also drive maladaptive states that amplify neuroinflammation. Microglial transitions are further shaped by receptor-mediated signaling and antigen presentation pathways that integrate environmental cues with functional responses. Adaptive immune cells contribute additional layers of regulation, with CD8+ and CD4+ T cells exerting neuroprotective or neurotoxic effects depending on disease context, activation state, and antigen specificity. The identification of granzyme K-expressing CD8+ T cells in several neurodegenerative conditions highlights the growing recognition that distinct T cell subsets may have specialized roles in disease. Aging, repetitive head injury, and viral infection further alter microglial phenotypes, weaken barrier integrity, promote T cell recruitment, and prime the CNS for chronic inflammation. In this review, we synthesize current knowledge of innate and adaptive immune mechanisms in neurodegeneration, examine how external factors influence these responses, and consider how these insights may guide future therapeutic strategies.
    DOI:  https://doi.org/10.1172/JCI199850
  35. Neural Regen Res. 2026 Apr 14.
    Multi-omics analysis of changes in the microbiota-gut- spinal cord axis in spinal cord injury.
    Yingli Jing, Fan Bai, Zihan Li, Qiuying Wang, Yan Li, Weijin Liu, Shuangyue Zhang, Chen Gao, Yan Yu.
      A growing body of research demonstrates the critical involvement of gut microbiota in the initiation and progression of central nervous system disorders. Notably, gut dysbiosis has been shown to impair immune responses, metabolic pathways, and behavioral phenotypes, positioning it as a key focus in contemporary central nervous system disease research. In this study, we aimed to elucidate the pathological and physiological processes by which microbiota-gut-brain communication mediates neural repair, particularly in the context of secondary injury after spinal cord injury. We established a traumatic spinal cord injury model at thoracic level 10 in mice. Neurological restoration in spinal cord injury mice was evaluated using behavioral testing and histopathological analysis in a time-dependent manner. The gut microbiota and short-chain fatty acids were analyzed via 16S rDNA sequencing and gas chromatography-mass spectrometry, respectively. Gene expression profiling of the colon was conducted through transcriptome sequencing. The expression levels of short-chain fatty acid-related receptors and transporters were detected via quantitative polymerase chain reaction. Serum cytokine profiles were analyzed via a cytometric bead array. 16S rDNA sequencing showed dynamic alterations in the gut microbiota at different stages after spinal cord injury, and indicated a lack of gut microbial recovery following injury. Moreover, targeted metabolomic analysis demonstrated that the levels of major short-chain fatty acids (acetic acid, propionic acid, and butyric acid) fluctuated across different phases after spinal cord injury, exhibiting a trend consistent with observed behavioral changes. Transcriptome sequencing showed that the gut exhibited different types of immune responses at different phases following injury and that the humoral immune response, innate immune response, and adaptive immune response dominated during the acute, subacute, and chronic phases, respectively. These responses were accompanied by alterations in short-chain fatty acid receptor and transporter profiles in the colon and cytokine profiles in the serum. Integrated spearman correlation analysis showed that changes in the gut microbiota and metabolite-short-chain fatty acid interactions were significantly correlated with behavioral outcomes, which suggests that gut dysbiosis might have crucial effects on neural repair through short-chain-fatty-acid-mediated secondary injury. The findings of this study provide a comprehensive map of microbiota-gut-spinal cord axis alterations after spinal cord injury, and suggest novel therapeutic strategies for mediating secondary injury, including alterations in the gut microbiota and metabolites.
    Keywords:  behavioral phenotypes; cytokine profiles; immune responses; microbiota-host interaction; microbiota–gut–spinal cord axis; neurological recovery; secondary injury; short-chain fatty acids; spinal cord injury; temporal dynamics
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00739
  36. Front Aging Neurosci. 2026 ;18 1784115
    Autologous SVF therapy modulates neuroinflammation in ALS: phase I trial demonstrating safety and CSF biomarker dynamics.
    Ruixia Li, Lin Wang, Wendi Bu, Xu Zhang, Xiaojing Li, Jing Li, Jiahui Shen, Jingwei Li, Zenglin Cai.
       Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with limited treatments. Stromal vascular fraction (SVF), a cell population derived from autologous adipose tissue, exhibits multimodal immunomodulatory and neuroprotective properties, positioning it as a promising therapeutic candidate.
    Methods: This trial aimed to assess autologous stromal vascular fraction (SVF) safety and efficacy in patients with ALS. 26 patients received combined intravenous (0.5 × 106 cells/kg) and intrathecal (20 × 106 cells) autologous SVF (An exploratory second dose of SVF was administered intrathecally to three patients 45 days later). The trial is registered with the Chinese Clinical Trial Registry (ChiCTR2400091754).
    Results: SVF administration was well-tolerated. Five mild adverse events (adverse events, AEs) (subcutaneous bleeding, headache, and low-grade fever) occurred, with no serious AEs reported. Although ALSFRS-R scores showed non-significant improvement post-treatment, 15/26 participants (57.7%) self-reported symptomatic improvement after treatment. Critically, cerebrospinal fluid biomarker analysis revealed significant reductions in neurofilament light chain (NfL; Δ530.29 pg/mL, P = 0.039) and glial fibrillary acidic protein (GFAP; Δ622.23 pg/mL, P = 0.038), indicating attenuation of neuroaxonal degeneration and astroglial activation. While ALSFRS-R scores showed no significant change (Δ-0.53, P = 0.384), prognostic modeling identified female sex (OR = 0.011, P = 0.008) and shorter disease duration (OR = 1.35/month, P = 0.005) as predictors of response. Three patients who underwent the second treatment were well tolerated without any adverse events.
    Conclusion: These findings indicate that Autologous SVF therapy might possess an acceptable safety profile for patients with ALS. The significant reduction in CSF NfL and GFAP levels provides objective evidence of their potential neuroprotective effects that modulates ALS-relevant neuroinflammation pathways. Female participants and those with shorter disease duration may derive greater benefits.
    Keywords:  amyotrophic lateral sclerosis; amyotrophic lateral sclerosis functional rating scale; glial fibrillary acidic protein; neurofilament light chain; stromal vascular fraction
    DOI:  https://doi.org/10.3389/fnagi.2026.1784115
  37. Eur J Neurol. 2026 Apr;33(4): e70595
    Erythrocyte Fragility in Progressive Multiple Sclerosis.
    Carmen Jacob, Thomas E Williams, Charlotte M Stuart, Aviva Witkover, Simon Hametner, Hans Lassmann, Charles R M Bangham, Jeremy Chataway, Ian Galea.
       BACKGROUND: Aberrant iron homeostasis is increasingly recognized as a key pathological feature in progressive multiple sclerosis (MS). Although the source of excess brain iron remains unclear, haemoglobin is one possible source. To test this hypothesis, we conducted a case-control study to determine whether erythrocytes are more fragile in people with progressive MS (PwPMS) and examined associations between erythrocyte fragility and brain atrophy.
    METHODS: PwPMS and control individuals were recruited from two centres. Two measures of erythrocyte fragility were assessed at baseline: the Median Corpuscular Fragility (MCF) and haemolysis curve slope. A subset of PwPMS in one centre underwent MR imaging at the same time as osmotic fragility testing and annually for three years thereafter.
    RESULTS: A total of 174 participants were included (75 PwPMS, 99 controls), with MRI data available for 44 PwPMS. No significant differences in the MCF were observed between PwPMS and controls in either the full or age-matched cohorts. However, the haemolysis curve slope in PwPMS was less steep than healthy controls (median PwPMS = -24.76, controls = -28.73, p = 0.017), consistent with a subpopulation of fragile erythrocytes, with a similar trend in the age-matched subset (p = 0.056). Erythrocyte fragility was associated with normalized whole brain volume at the time of osmotic fragility testing and up to three years thereafter.
    CONCLUSIONS: Extracellular haemoglobin from lysis of an erythrocyte subpopulation may contribute to neurodegeneration in progressive MS. Further research is warranted to elucidate the interplay between erythrocyte health, inflammation and neurodegeneration, which may open avenues for novel therapeutic strategies.
    Keywords:  erythrocyte; haemoglobin; haemolysis; multiple sclerosis; osmotic fragility
    DOI:  https://doi.org/10.1111/ene.70595
  38. Mol Psychiatry. 2026 Apr 16.
    Exploring the lung-brain axis in perioperative neurocognitive disorders: a potential therapeutic target.
    Penghui Wei, Tong Zhu, Kenji Hashimoto, Min Jia, Jian-Jun Yang.
      Perioperative neurocognitive disorders (PND), primarily including postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), are common and serious complications in elderly surgical patients. However, the exact mechanisms underlying PND are not fully understood. The lung-brain axis has recently been recognized as an important pathway in neurodegenerative diseases such as Alzheimer's disease (AD). Given that PND shares pathological features with AD, such as amyloid-β (Aβ) accumulation, the lung-brain axis may also represent a plausible mechanistic contributor to PND. Furthermore, elderly surgical patients often receive inhalation anesthetics and undergo mechanical ventilation during general anesthesia, which directly affect the lungs and may alter the pulmonary microenvironment. Therefore, we hypothesize that the lung-brain axis plays a role in the development of PND. In this article, we discuss potential mechanisms by which surgery and anesthesia-especially inhalation anesthetics and mechanical ventilation-may influence cognitive function via the lung-brain axis. Potential mechanisms include changes in the pulmonary microbiota, secretion of brain-derived neurotrophic factor, and lung-derived inflammatory responses. These pathways may disrupt the blood-brain barrier, promote neuroinflammation, and exacerbate Aβ deposition, ultimately leading to cognitive impairment. Exploring the role of the lung-brain axis could provide new insights into PND pathophysiology and reveal potential targets for prevention and treatment of PND by targeting pulmonary-mediated cascades.
    Keywords:  BDNF; Lung-Brain axis; Perioperative neurocognitive disorders; Postoperative delirium; Pulmonary inflammation; Pulmonary microenvironment
    DOI:  https://doi.org/10.1038/s41380-026-03604-5
  39. Front Neurosci. 2026 ;20 1753609
    Involvement of the reticulospinal tract in the pathogenesis of spasticity after stroke and spinal cord injury.
    Sachiko Lee-Hotta.
      Spasticity occurs due to central nervous system (CNS) injuries such as stroke, spinal cord injury, cerebral palsy, or multiple sclerosis. Following CNS injury, spasticity does not appear immediately but emerges several days to weeks later and is believed to be the result of maladaptive changes due to neuroplastic alterations. Previously, research on the pathophysiology of spasticity has primarily focused on the spinal cord, leading to the elucidation of its mechanisms. Although the involvement of upper motor neurons has been suggested, definitive studies on the underlying pathophysiology have not been reported. In recent years, brainstem reticular formation has been identified as a region undergoing active plastic changes following a CNS injury. Although evidence remains limited and controversial, increasing numbers of studies suggest that plastic changes in brainstem reticular formation may be involved in the onset of spasticity. This review outlines the pathophysiological similarities and differences in spasticity between stroke and spinal cord injury, while summarizing recent studies on plastic changes in brainstem reticular formation and the onset of spasticity, including studies of humans and primates, as well as rodents. It organizes and examines the points of contention regarding the differences in outcomes between these two groups.
    Keywords:  neuronal plasticity; reticular formation; reticulospinal tract; spasticity; spinal cord injury; stroke
    DOI:  https://doi.org/10.3389/fnins.2026.1753609
  40. Cells. 2026 Mar 28. pii: 603. [Epub ahead of print]15(7):
    Irisin as a Regulator of Brain Energy Homeostasis: Implications for Age-Related Neurodegenerative Diseases.
    Bartosz Osuch, Patrycja Młotkowska, Elżbieta Marciniak, Tomasz Misztal.
      Aging is associated with disturbances in brain energy metabolism, mitochondrial dysfunction, and increased oxidative stress, all of which increase neuronal vulnerability and contribute to the development of neurodegenerative disorders. Growing evidence indicates that physical exercise exerts neuroprotective effects through the release of exerkines-exercise-induced signaling molecules that mediate communication between peripheral tissues and the brain. Among them, irisin, a proteolytic cleavage product of the membrane protein FNDC5, has emerged as an important mediator of the muscle-brain axis. This review summarizes current knowledge on the molecular mechanisms underlying irisin activity in the central nervous system, with particular emphasis on the AMPK-PGC-1α-FNDC5/BDNF signaling axis, rapid receptor-mediated pathways involving the cAMP/PKA/CREB and ERK/CREB cascades, and the regulation of mitochondrial homeostasis, including biogenesis, dynamics, autophagy, and mitophagy. Experimental studies suggest that irisin may improve neuroplasticity, neuronal survival, mitochondrial function, and reduce oxidative stress, thereby alleviating cognitive deficits in models of aging and neurodegeneration. Although the precise receptor mechanisms and intracellular signaling events remain incompletely understood, accumulating evidence identifies irisin as a promising therapeutic target linking metabolic adaptation with neuroprotection. Further investigation of irisin-dependent pathways may facilitate the development of novel strategies aimed at preserving brain function and delaying the progression of age-related neurodegenerative diseases.
    Keywords:  AMPK–PGC-1α; BDNF; FNDC5; irisin; mitochondrial homeostasis; mitophagy; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/cells15070603
  41. J Drug Target. 2026 Apr 16. 1-40
    Nanomedicines for Neurodegenerative Ageing: Nasal Delivery Innovations for Alzheimer's and Parkinson's Disease.
    Rajshekher Upadhyay, Ayush Jain, Karthik Trivedi, Madhuri Desavathu.
      Alzheimer's disease and Parkinson's disease are progressive, age-related neurodegenerative disorders with increasing global prevalence, yet their treatment remains challenging despite the availability of multiple therapeutic agents. Conventional formulations are often limited by poor solubility, restricted blood-brain barrier penetration, extensive first-pass metabolism, short elimination half-life, low brain bioavailability, and systemic adverse effects. In recent years, the nose-to-brain route has emerged as a promising strategy for delivering therapeutics directly to the brain. This approach offers non-invasive administration, rapid onset of action, direct brain targeting via olfactory and trigeminal pathways, reduced systemic exposure, bypassing of first-pass metabolism, improved bioavailability, and enhanced patient compliance. To exploit these advantages, a variety of biodegradable nanocarrier systems have been investigated, including lipid-based and polymer-based nanoparticles, nasal gel-based systems, nanoemulsions, nanosuspensions, hybrid nanoparticles, and nasal sprays. This review provides a comprehensive synthesis of preclinical studies evaluating nose-to-brain nanocarrier-based delivery strategies for Alzheimer's and Parkinson's disease, with particular emphasis on their pharmacokinetic and pharmacodynamic performance. Collectively, the evidence indicates that nose-to-brain nanocarriers can effectively address key limitations of conventional therapies by enhancing brain targeting and therapeutic efficacy. However, successful clinical translation will require addressing formulation-related challenges such as mucociliary clearance, nasal irritation, burst drug release, and long-term safety, alongside well-designed clinical studies. Future research should therefore focus on exploring emerging delivery platforms to further advance nose-to-brain strategies for the management of neurodegenerative diseases.
    Keywords:  Bioavailability; Intranasal; Neurodegeneration; Nose-to-brain; Pharmacokinetics; lipidic nanoparticles; polymeric nanoparticles
    DOI:  https://doi.org/10.1080/1061186X.2026.2659210
  42. Aging Dis. 2026 Apr 13.
    Extension of Lifespan and Amelioration of Alzheimer's Disease Phenotypes by Genetic Manipulation of Mitochondrial NAD+/NADH Ratio.
    Suman Rimal, Jae-Hyuk Lee, Yanzi He, Bingwei Lu.
      Aging remains the most significant risk factor for common neurodegenerative diseases including Alzheimer's disease (AD). According to the geroscience hypothesis, aging is malleable and that by targeting basic aging physiology, we can alleviate many of the age-related chronic diseases. The common mechanisms driving aging and age-related diseases remain poorly defined. Mitochondrial dysfunction is recognized as a fundamental hallmark of aging, and recent studies implicate mitochondrial reverse electron transport (RET) as a driver of aging. The key outcomes of RET, increased ROS and decreased NAD+/NADH ratio, have both been associated with aging and age-related disease, but the causal relationship remains uncertain. Here we applied causal metabolism to test the role of mitochondrial NAD+/NADH in aging and AD, using Drosophila as a model system. By using a mitochondrial targeted version of Lactobacillus brevis NADH oxidase (LbNox) to boost mitochondrial NAD+/NADH ratio independent of the energy state of the cell, we found that increasing mitochondrial NAD+/NADH ratio in neuronal or muscle tissues is sufficient to extend lifespan. Moreover, boosting mitochondrial NAD+/NADH ratio is beneficial in two independent models of AD, rescuing the proteostasis failure, locomotor and cognitive deficits, and lifespan shortening in these models. Our results identify altered mitochondrial NAD+/NADH ratio as a major contributor to the biological effects of RET on aging and age-related diseases and a potential therapeutic target.
    DOI:  https://doi.org/10.14336/AD.2026.0011
  43. Neurobiol Dis. 2026 Apr 15. pii: S0969-9961(26)00145-2. [Epub ahead of print] 107400
    Histamine H4 receptor in neuroinflammation: Dual roles in multiple sclerosis and Parkinson's disease.
    Wen-Jie Yan, Yan-Li Yang, Wen Yan, Si-Yuan Tian, Ying Zi, Guo-Jin Liu, Ze-An Yi, Ruo-Xi Shao, Chen-Yue Shi, Ling Shan, Qian-Xing Zhuang.
      Neuroinflammation plays a pivotal role in the progression of neurodegenerative disorders such as multiple sclerosis (MS) and Parkinson's disease (PD), primarily through a self-amplifying positive feedback loop between inflammation and neurodegeneration. The histamine H4 receptor (H4R), expressed on both peripheral immune cells and central microglia, serves as a critical molecular interface linking peripheral immunity to central nervous system inflammation. This review provides a systematic analysis of the context-dependent, dual roles of H4R in neuroinflammatory processes underlying MS and PD. In the context of MS and its experimental autoimmune encephalomyelitis (EAE) model, H4R activation promotes NF-κB signaling and upregulates pro-inflammatory mediators including TNF-α and IL-6, thereby driving the differentiation of pathogenic T-helper subsets (Th1, Th9, and Th17) and exacerbating disease pathology. Paradoxically, H4R signaling may also support early immune homeostasis by facilitating the expansion and functional maturation of regulatory T cells. In PD, elevated H4R expression correlates with increased disease severity. H4R activation drives microglial polarization toward a pro-inflammatory phenotype and stimulates the release of inflammatory cytokines via NF-κB and MAPK signaling pathways, ultimately contributing to dopaminergic neuron loss. Conversely, under specific physiological or pharmacological conditions, H4R engagement can promote anti-inflammatory microglial polarization through the JAK/STAT/PI3K/Akt signaling cascade. The functional complexity of H4R arises from factors such as cell-type specificity, disease stage, ligand-biased signaling, and variations across experimental models. A deeper understanding of the dual regulatory mechanisms of H4R and its therapeutic potential will offer valuable insights for the development of novel strategies targeting neuroinflammatory pathways.
    Keywords:  Histamine H4 receptor; Microglia; Multiple sclerosis; Neuroinflammation; Parkinsons disease
    DOI:  https://doi.org/10.1016/j.nbd.2026.107400
  44. Front Aging Neurosci. 2026 ;18 1782720
    Gut microbiota and cognitive decline: a scoping review of microbial mechanisms and adaptive responses in dementia.
    Giovanni Luca Cipriano, Alessandro Grimaldi, Angela Marra, Angelo Quartarone, Giuseppa Maresca.
      Dementia is a progressive disease that results in a loss of mental capacity. Some of the most affected cognitive skills are memory, orientation, and language. These skills are also associated with behavioral shifts such as increased agitation and apathy, worsening the affected person's quality of life. The most common type of dementia is Alzheimer's disease, and it is especially concerning in older adults. Alzheimer's is characterized by the formation of beta-amyloid plaques and neurofibrillary tangles that are made of hyperphosphorylated tau proteins. These plaques and tangles lead to inflammation in the central nervous system, damage to the connections between neurons, and overall degeneration of the nervous system. Newer studies have started to identify the gut microbiome and the gut-brain axis as components critical to the progression of neurodegenerative diseases. Dysbiosis, which is characterized by an imbalance or loss of microbial diversity in the gut, has been attributed to the worsening of neurodegenerative diseases. The gut microbiome has been shown to have a large impact on the brain and how it responds neurochemically. An imbalance in the gut microbiome has also been shown to lead a person to emotional and cognitive dysfunction. It has been shown that in dementia patients, there is also an associated intestinal dysbiosis and increased inflammation systemically and within the brain. Certain gut bacteria stimulate the production of pro- inflammatory cytokines and neuroinflammation, which is a defining characteristic of diseases associated with dementia. This review is focused on three main aspects in which dysbiosis is related to cognitive decline.
    Keywords:  Alzheimer’s disease; cognitive decline; dementia; dysbiosis; gut microbiota; gut-brain axis; neuroinflammation
    DOI:  https://doi.org/10.3389/fnagi.2026.1782720
  45. Curr Opin Infect Dis. 2026 Mar 16.
    Neurological manifestations of respiratory viral infections.
    Irene Mora Castaño, Rodrigo Hasbun.
       PURPOSE OF REVIEW: This review summarizes current evidence on the general epidemiology, routes of central nervous system (CNS) invasion, clinical manifestations, diagnostic approaches, and treatment considerations associated with neurological complications of respiratory viral infections. Greater awareness of the neurological impact of respiratory viral infections is crucial to improving patient outcomes and mitigating long-term burden of these diseases.
    RECENT FINDINGS: Recent studies have reinforced the association between respiratory viral infections and a broad spectrum of neurological complications. Evidence accumulated during and after the coronavirus disease 2019 (COVID-19) pandemic has expanded this awareness, and emerging data suggest that immune-mediated mechanisms such as glial cell activation, rather than direct viral neurotropism alone, play a central role in CNS injury. Although diagnostic limitations still exist, some advances have been made to increase specificity of resources available for clinicians, particularly PCR and immunologic profiling. Furthermore, vaccination against certain respiratory viruses may reduce the risk of subsequent neurodegenerative disease, highlighting the potential impact of preventive strategies on long-term neurological burden.
    SUMMARY: Establishing causality between respiratory viral infections and subsequent neurological dysfunction remains challenging given the ubiquitous nature of many respiratory viruses and their capacity to cause lifelong latent or persistent infection. Even though some efforts have been made to optimize diagnosis and treatment, addressing these challenges will require further coordinated efforts across clinicians, researchers and healthcare policymakers.
    Keywords:  encephalitis; neurological manifestations; postinfectious neurological sequelae; respiratory viral infections; virus related neuroinflammation
    DOI:  https://doi.org/10.1097/QCO.0000000000001189
  46. Brain Res Bull. 2026 Apr 13. pii: S0361-9230(26)00173-5. [Epub ahead of print] 111887
    The Dual Role of Microglia in Neurodegenerative Diseases: A Review.
    Nanke Zhang, Nan Xiong, Yanlin He, Lele Zhou.
       BACKGROUND: Microglial activation has increasingly been recognized as a central hub in the pathogenesis of neurodegenerative diseases, where it exerts dynamic regulatory roles characterized by a contest between neuroprotective and neurotoxic actions. However, the precise process underlying this interplay between the two opposing effects remains incompletely elucidated.
    RESULTS: Moderate activation of microglia prevents the accumulation of neurotoxic substances, such as cellular debris and misfolded proteins, promotes neuronal survival by secreting neurotrophic factors, and induces self-limiting inflammation that exerts neuroprotective and repair-promoting effects. In contrast, chronic and persistent microglial activation driven by sustained elevations of pro-inflammatory cytokines, cGAS-STING-mediated DNA sensing, hyperactivation of membrane receptors (e.g., TREM2 and CX3CR1), mitochondrial dysfunction, accumulation of disease-associated proteins, and the emergence of regulatory lectins like Galectin-3, accelerates the progression of neurodegenerative diseases. Through multi-targeted and multi-mechanistic interventions aimed at enhancing microglial phagocytic activity, inhibiting aberrant complement-mediated synaptic pruning (C1q/C3/CR3), reducing neuroinflammation, modulating immune checkpoints (e.g., CD33 and TIM-3)-it is possible to preserve microglial clearance of pathological factors and support neuronal repair. These precision strategies prevent the erroneous engulfment of healthy synapses and promote M2-like polarization，thereby optimizing neuroprotective effects, and delaying or ameliorating the progression of neurodegenerative diseases.
    CONCLUSIONS: This review outlines the dynamic "double-edged sword" role of microglia in neurodegenerative diseases and systematically summarizes the clinical and multi-targeted intervention strategies designed to precisely modulate their functions and skew them toward a neuroprotective phenotype.
    Keywords:  Dual role; Microglia; Neurodegenerative diseases; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.brainresbull.2026.111887
  47. J Leukoc Biol. 2026 Apr 09. pii: qiag047. [Epub ahead of print]
    Tissue Context as a Determinant of Trained Innate Immunity: A Conserved Molecular Toolkit with Divergent Functional Outputs.
    Mary A Oliver, Xenia D Davis, Julia K Bohannon.
      Trained innate immunity (TI) challenges the traditional view that adaptive immune cells are solely responsible for establishing immune memory. Instead, innate immune cells can develop a form of memory through persistent epigenetic, metabolic, and antimicrobial modifications, enabling them to respond to secondary challenges in a nonspecific manner. While the molecular mechanisms underlying this trained response have been extensively characterized and are well understood, the intrinsic cellular programs driving trained immunity have not been clearly delineated. Further, the influence of tissue-specific microenvironments remains underexplored. Evidence indicates that the heterogeneity observed in trained immune responses is partly attributable to the functional outcomes shaped by trained immunity within diverse tissue microenvironments, underscoring the complexity and context-dependent nature of this adaptive process. In this review, we explore that TI uses a conserved molecular toolkit whose functional output is dictated by tissue microenvironment. Signals such as oxygen tension, microbiota, local metabolites, cytokine release, and damage-associated molecular patterns can also shape trained innate immunity. The resulting outcomes range from increased antimicrobial defense to maladaptive responses that lead to chronic inflammation and tissue damage. Together, we synthesize findings from hematopoiesis and tissue-resident macrophage biology, emphasizing how immunometabolism and epigenetic mechanisms underpin tissue-specific models of TI. This comprehensive framework resolves contradictions observed across different organs and disease states, positioning tissue instruction as a pivotal determinant of innate immune memory. It demonstrates that trained immunity programs are intricately adapted to tissue niches, with profound implications for infection control, inflammatory diseases, tissue regeneration, and the precise therapeutic targeting of innate immune cells.
    Keywords:  Epigenetics; Immunometabolism; Tissue-resident macrophage; Trained innate immunity
    DOI:  https://doi.org/10.1093/jleuko/qiag047
  48. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Apr 13. 1-3
    Fast and controlled access to tofersen for SOD1-related amyotrophic lateral sclerosis in The Netherlands; experiences using the orphan drug access protocol.
    Sean W Willemse, Carla E M Hollak, Niels D Reijnhout, Carelle C Reparon-Schuijt, Anke A M G Pisters-van Roy, Koen C Demaegd, Ruben P A van Eijk, Leonard H van Den Berg, Michael A van Es.
      
    DOI:  https://doi.org/10.1080/21678421.2026.2655738
  49. Neurol Neurochir Pol. 2026 Apr 17.
    Disease-modifying treatment for multiple sclerosis in Poland in a European context: current practices and therapeutic strategies.
    Monika Adamczyk-Sowa, Martyna Lis.
      Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system and the leading cause of non-traumatic disability in young adults. In Poland, MS represents a significant neurological and public health challenge. Although treatment principles for MS are largely based on international guidelines, their implementation varies across countries due to differences in healthcare organization and access to therapies. Current treatment algorithms in Poland include both platform agents, such as interferon beta, glatiramer acetate, fumarates, and teriflunomide, as well as high-efficacy therapies, including monoclonal antibodies (e.g., ocrelizumab, ofatumumab, ublituximab, alemtuzumab, natalizumab) and oral agents (e.g., fingolimod, cladribine, ozanimod, ponesimod). Therapeutic decisions typically follow either an escalation strategy or an early intensive approach, depending on disease activity, prognostic factors, and reimbursement criteria. In addition, treatment priorities vary depending on the disease phenotype: in relapsing-remitting MS (RRMS), the aim is to reduce relapse rates and delay disability progression, whereas in progressive forms, such as primary progressive MS (PPMS) and secondary progressive MS (SPMS), the goal is to slow disease progression and preserve daily functioning. With an expanding range of therapeutic options, European clinical experience in the management of different MS phenotypes, particularly RRMS, reflects an individualized treatment approach. In routine practice, therapeutic decisions are primarily guided by disease activity, with high-efficacy therapies considered early in selected patients; similar principles inform real-world clinical practice in Poland. This review offers practical guidance for clinicians and provides therapeutic algorithms designed to support the management of patients with MS. The future development of MS management in Poland will depend on expanding access to innovative therapies, advancing biomarker research, and implementing the latest diagnostic criteria for MS. European treatment recommendations will continue to provide an important framework supporting high-quality care and early intervention for people with MS.
    Keywords:  NHF B.29; PIRA; disease-modifying therapy; multiple sclerosis; personalized medicine; relapse-associated worsening; smoldering MS
    DOI:  https://doi.org/10.5603/pjnns.110291
  50. Int J Mol Sci. 2026 Mar 25. pii: 2993. [Epub ahead of print]27(7):
    Copper Dyshomeostasis Affects α-Synuclein Clearance Mechanisms in Parkinson's Disease: Insights from In Vitro Models and Translational Evidence.
    Debora Musarò, Marco Greco, Martina Lanza, Marina Damato, Michele Maffia.
      Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic neurons and the accumulation of α-synuclein-rich inclusions, largely resulting from impaired protein clearance mechanisms. Copper is an essential redox-active metal in the central nervous system (CNS), but alterations in its homeostasis can promote oxidative stress, mitochondrial dysfunction, and proteostatic failure. In vitro studies indicate that copper can promote α-synuclein misfolding, enhance oxidative stress, and interfere with both the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP). In this review, we critically evaluate mechanistic evidence from cellular models, integrating available animal and clinical data to assess the biological significance of copper-mediated impairment of α-synuclein clearance. We highlight the current research, identify methodological limitations, and discuss whether copper imbalance acts as a primary pathogenic trigger or as a disease-modifying amplifier of proteostatic failure. Furthermore, we consider the translational implications of selectively modulating intracellular copper pools as a therapeutic strategy in PD. Finally, we will highlight unresolved issues, methodological limitations, and emerging targeted therapeutic prospects.
    Keywords:  Parkinson’s disease; alpha-synuclein; autophagy; copper; ubiquitin proteasome system
    DOI:  https://doi.org/10.3390/ijms27072993
  51. J Anim Sci. 2026 Apr 10. pii: skag117. [Epub ahead of print]
    Effects of gut barrier dysfunction during a viral respiratory disease challenge on immune function of feedlot beef calves.
    R C Foster, V N Gouvêa, M R Beck, O J Benitez, J Diaz-Delgado, K F Migl, F Rosa, M A Scott, N S Long, J T Pennington, R F Cooke.
      Feedlot morbidity and mortality have increased in recent decades, driven in part by the prevalence of bovine respiratory disease (BRD). Research on gut barrier dysfunction (GBD) reveals similarities in predisposing factors and etiopathogenic mechanisms to BRD. This overlap suggests that GBD may serve as a predisposing factor, increasing susceptibility to BRD. To explore this connection, 15 Angus × Holstein heifers (initial body weight = 475 ± 12 kg) were used in a randomized complete block design experiment to evaluate the effects of induced changes in intestinal permeability on immune responsiveness during a viral respiratory disease challenge. Treatments were control (CT; n = 7) or GBD (n = 8), where GBD heifers underwent a protocol to increase gut permeability using aspirin (100 mg/kg of body weight every 12 hours for 4 consecutive days). Daily dry matter intake and average daily vaginal temperature (DVT) were continuously recorded. After aspirin withdrawal, all heifers were inoculated with bovine herpesvirus-1. Complete blood count, cytokines, acute-phase proteins (APP), cortisol, and intestinal morphology were evaluated. Heifer was considered the experimental unit for all analyses. The statistical model included the fixed effect of treatment and hour/day and the resultant interactions, run and heifer (treatment) were used as random effects, and hour or day was the term for all repeated statements, and heifer (treatment) was the subject. Aspirin administration increased gut permeability in GBD heifers, as evidenced by greater plasma Chromium-EDTA recovery (P = 0.02) and increased lipopolysaccharide-binding protein concentration (treatment × hour; P < 0.01) early in the disease challenge. Compared to CT, GBD heifers tended to exhibit decreased DVT (P = 0.10) and haptoglobin concentration (treatment × hour; P = 0.06) by the end of the disease challenge. No significant differences were observed in serum amyloid A, interleukin-6, tumor necrosis factor-α, interleukin-10, or cortisol concentration (P ≥ 0.20). A tendency for decreased white blood cell (P = 0.08) and lymphocyte counts (treatment × hour; P = 0.08) in GBD heifers was observed. There were no effects of treatments on intestinal morphology (P ≥ 0.16). These findings suggest that increased gut permeability influences immune responses by reducing the febrile response and decreasing the production of some APP. Greater emphasis on gut health could improve disease outcomes in BRD management.
    Keywords:  Bovine Respiratory Disease; Immune Response; Inflammation; Leaky Gut; Stress
    DOI:  https://doi.org/10.1093/jas/skag117
  52. Drug Discov Today. 2026 Apr 10. pii: S1359-6446(26)00072-3. [Epub ahead of print] 104667
    Artificial intelligence revolutionizing CNS drug discovery and development.
    Md E K Talukder, Mohammad R Islam, Saghir Ali, Jia Zhou, Andrew A Bolinger.
      Central nervous system (CNS) drug discovery faces high attrition rates, long timelines and substantial costs due to complex disease biology and the difficulties in safe drug delivery. Conventional CNS processes remain slow and trial-and-error driven. These challenges often result in poor brain penetration, off-target toxicity or limited efficacy after years of development. Recently, the integration of artificial intelligence (AI) with computer-aided drug design (CADD) has enabled more precise and scalable approaches for therapeutic development. AI-powered tools prioritize high-value analogs, streamlining design and optimization. This review provides an overview of how AI technologies are redefining early-stage CNS drug discovery, particularly for complex and underserved neurological diseases.
    Keywords:  artificial intelligence; central nervous system; clinical trials; computer-aided drug design; deep learning; machine learning; medicinal chemistry; neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.drudis.2026.104667
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