bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–03–22
fifty-one papers selected by
Luca Bolliger, lxBio
  1. Splicing the narrative: alternative TARDBP splicing and its relation to neurodegeneration in ALS and FTD.
  2. TDP-43 impairs glycolysis by sequestering hexokinase 1 in amyotrophic lateral sclerosis.
  3. Reduced nuclear TDP-43 and cytoplasmic DLK1 as markers of motor neuron degeneration in amyotrophic lateral sclerosis.
  4. Ubiquitin signatures on aggregating proteins in neurodegeneration.
  5. Approaching Serious Illness Conversations in Amyotrophic Lateral Sclerosis Using Telehealth: A Practical Guide.
  6. From Refractory Epilepsy to Neurodegeneration: Emerging Mechanistic and Clinical Insights Into the Ketogenic Diet.
  7. Systemic dysregulation of apolipoproteins in amyotrophic lateral sclerosis serum.
  8. High-throughput screening of ALS patient iPSC-derived spinal motor neurons identifies novel compounds that increase neurofilament light chain expression.
  9. The role of IRF5 in Microglia-Mediated neuroinflammation in ALS.
  10. Decoding neurodegeneration one cell at a time.
  11. Aldh3a1-mediated detoxification of reactive aldehydes contributes to distinct muscle responses to amyotrophic lateral sclerosis progression.
  12. Plasma proteomic trajectories before the onset of neurodegenerative diseases.
  13. Safety and Efficacy of PrimeC in Amyotrophic Lateral Sclerosis: The PARADIGM Randomized Clinical Trial.
  14. Sarcopenia in amyotrophic lateral sclerosis: a key predictor of respiratory dysfunction and disease progression.
  15. ALS mutations disrupt self-association between the ubiquilin STI1 hydrophobic groove and internal placeholder sequences.
  16. ALS motor phenotypes: a revised 'OPM' classification.
  17. High Prevalence of SOD1 Pathogenic Variants in the UK Biobank: Implications for Early Intervention in Amyotrophic Lateral Sclerosis.
  18. Identification of tofersen PD-response biomarkers in VALOR clinical trial CSF via multiplexed quantitative proteomics.
  19. Overcoming the blood‒brain barrier: nanomedicine strategies for targeted delivery and multimodal therapy in Alzheimer's disease.
  20. Targeting lipocalin-2 for multiple sclerosis: a dual role in diagnosis and therapy.
  21. Translating neurofilament light chain testing into clinical practice: a multidisciplinary implementation roadmap.
  22. From Environment to Symptoms: Mapping Premorbid Risk Factors onto Clinical Features of ALS in a Patient-Reported Database in China.
  23. Autophagy-exosome crosstalk in neurodegeneration: Mechanisms and therapeutic opportunities.
  24. Neuroprotective Effects of the Combination of Green Tea, Saffron, Docosahexaenoic Acid, and α-Lipoic Acid in an In Vitro Model of Parkinson's Disease.
  25. Naturally occurring antibodies against ASC reduced in Alzheimer's disease and alleviating AD-type pathology in APP/PS1 mouse.
  26. Identification of novel biomarkers for Alzheimer's disease: A deep learning omics-based approach to drug pair discovery and exploration of potential therapeutic targets.
  27. Targeting Epstein-Barr virus (EBV) for treatment of multiple sclerosis.
  28. Implanted brain-computer interface functionality during nighttime in late-stage amyotrophic lateral sclerosis.
  29. Decoding the biology of the blood-brain tumor barrier in brain cancer.
  30. Targeting neuroinflammation: itaconate and mesaconate as therapeutic strategies against H7N7 influenza-associated CNS damage.
  31. Blood-brain barrier-penetrative lipid nanoparticles enable systemic delivery of TRIM11 mRNA to disaggregate Tau in Alzheimer's disease models.
  32. How gut microbiota contribute to neuropsychiatric disorders: evidence from neuroimaging studies.
  33. The delivery challenge of adeno-associated virus vector-based gene therapies for neurological diseases.
  34. Circulating Toll-like receptor and cytokine profiles and genetic polymorphisms in a Chinese sepsis cohort: potential links to neuroinflammation and blood-brain barrier dysfunction.
  35. Recent advances in polymeric nanoparticle-mediated drug delivery system across the blood-brain barrier in Alzheimer's disease.
  36. Multiple sclerosis synaptic connectome: Insights from fluid biomarkers.
  37. A dynamic in vitro model of blood-brain barrier: effect of different polymeric nanoparticles on the crossing ability.
  38. Identifying priorities for a national motor neurone disease (amyotrophic lateral sclerosis) guideline: results from an Australian online survey.
  39. Synergy Feedback Control Predicts Walking Across Multiple Cycles.
  40. Metabolic-based therapeutic strategies to treat Huntington's disease.
  41. Measuring blood-brain barrier dysfunction: a critical appraisal of fluid biomarkers, in vitro models, in vivo imaging, and post-mortem approaches.
  42. Pharmacological Breakthroughs with Extracellular Vesicles-Based Nanomedicine: A Targeted Strategy to Cross the Blood-Brain Barrier in Alzheimer's Disease.
  43. The relationship between dietary patterns and neuroinflammation.
  44. TREM2 as a possible link between Alzheimer's disease and diabetes mellitus.
  45. The futility of the familiar: rethinking strategies for the development of small molecules for neurodegenerative disorders.
  46. Breaking Barriers: Advanced Pharmacological Mediators for Neuropsychiatric Disorders.
  47. Baicalin as a Multifunctional Regulator of Gut Health: Integrative Mechanisms Involving Inflammation, Barrier Integrity, and Gut-Organ Axis.
  48. Diet, gut microbiome, and cognition in neurodegeneration: a review and methodological framework.
  49. The role of zinc transporter 1 (ZnT1) in health and disease: From molecular mechanisms to therapeutic opportunities.
  50. Rewiring the Lung-CNS Axis After Spinal Cord Injury.
  51. Decoding the Blood-Brain Barrier: Innovative and Scalable Open-Source Machine Learning Model for Drug Permeability.
  1. J Clin Invest. 2026 Mar 16. pii: e199846. [Epub ahead of print]136(6):
    Splicing the narrative: alternative TARDBP splicing and its relation to neurodegeneration in ALS and FTD.
    Morgan R Miller, Megan Dykstra, Sami Barmada.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative diseases characterized by the nuclear clearance and cytoplasmic aggregation of transactive response DNA/RNA-binding protein of 43 kDa (TDP43). Alternative splicing of TARDBP, the gene encoding TDP43, leads to a surprising diversity of RNA and protein isoforms with unique functions and potential implications for disease pathogenesis. Here, we review the production, properties, and functional consequences of alternative splicing in the development of ALS and FTD, focusing primarily on TDP43 due to its integral connection with the pathogenesis of sporadic as well as familial forms of these diseases. We synthesize current evidence on the biology of alternative TARDBP splicing, highlight key questions regarding its role in TDP43 proteinopathies such as ALS and FTD, and touch on the larger phenomenon of alternative splicing and its relationship to disease.
    DOI:  https://doi.org/10.1172/JCI199846
  2. Acta Neuropathol. 2026 Mar 16. pii: 26. [Epub ahead of print]151(1):
    TDP-43 impairs glycolysis by sequestering hexokinase 1 in amyotrophic lateral sclerosis.
    Cassandra Barone, Rihua Wang, Sarah Cooke, Hang Pong Ng, Rodolfo S Ferreira, Helen C Miranda, Xin Qi.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and cytoplasmic mislocalization of TDP-43. While metabolic dysfunction is increasingly recognized in ALS, the mechanistic link between impaired energy metabolism and TDP-43 pathology remains unknown. Here, we show that cytoplasmic TDP-43 directly disrupts glycolysis by targeting hexokinase 1 (HK1), the first rate-limiting enzyme of the pathway. In cells expressing a TDP-43 variant lacking its nuclear localization signal and in patient-derived iPSC motor neurons, TDP-43 accumulation in the cytoplasm reduces glycolytic capacity, indicating a neuron-intrinsic metabolic defect. Across cellular models including patient-derived neurons, TDP-43 mutant mice, and postmortem spinal cord tissue from ALS patients, we observe consistent decreases in HK1 protein level, mitochondrial association, and enzymatic activity, despite unchanged transcript levels. Mechanistically, cytoplasmic TDP-43 directly binds to HK1, disassociating it from mitochondria and promoting its sequestration into insoluble aggregates. This mislocalization impairs glycolysis and increases neuronal vulnerability. Notably, compensation for HK1 loss reduces cytoplasmic TDP-43 and ubiquitin accumulation, improves motor performance, and prolongs survival in TDP-43-associated ALS models. Together, these findings identify a previously unrecognized mechanism by which TDP-43 impairs glycolysis through HK1 misregulation and highlight glycolytic restoration as a potential therapeutic strategy in ALS.
    Keywords:  Glucose; Metabolism; Motor neuron; Spinal cord
    DOI:  https://doi.org/10.1007/s00401-026-02996-6
  3. J Neuropathol Exp Neurol. 2026 Mar 19. pii: nlag017. [Epub ahead of print]
    Reduced nuclear TDP-43 and cytoplasmic DLK1 as markers of motor neuron degeneration in amyotrophic lateral sclerosis.
    Takahiro Takeda, Ai Ishikawa, Sayuri Kokubun, Yumiko Saito, Sagiri Isose, Kimiko Ito, Kimihito Arai, Satoshi Kuwabara, Kazuhiro Honda.
      Loss of upper and lower motor neurons (MNs) is a defining pathological feature underlying the clinical manifestations of amyotrophic lateral sclerosis (ALS). However, the differences in MN loss and TDP-43 pathology between these areas in ALS patients remain unclear. This study included 7 patients with ALS and 3 controls from consecutive autopsies. The cell density and regional density of TDP-43-positive inclusions in 4 upper MN areas and their anatomically corresponding lower MN areas were measured. The numbers of large cells with loss of nuclear TDP-43 and cytoplasmic delta-like-1 homolog (DLK1) were counted. The results showed severe MN loss in both upper and lower MN areas. However, TDP-43-positive inclusions differed markedly, that is they were rare in upper MNs but abundant in lower MN. In upper MN areas, TDP-43 density was not associated with the residual rate of MNs, whereas in lower MN areas, the density in MNs was associated with the cell residual rate. Significantly higher numbers of MNs lacking nuclear TDP-43 and cytoplasmic DLK1 were observed in the upper and lower MN regions in ALS vs controls. These findings suggest that these morphological changes may be closely related to motor neuron vulnerability and may be mechanistic contributors to ALS development.
    Keywords:  DLK1; TDP-43 pathology; amyotrophic lateral sclerosis; cytoplasmic inclusions; motor neuron degeneration; neuropathology
    DOI:  https://doi.org/10.1093/jnen/nlag017
  4. Essays Biochem. 2025 Dec 22. pii: EBC20253046. [Epub ahead of print]69(5):
    Ubiquitin signatures on aggregating proteins in neurodegeneration.
    Subhashree Sahoo, Amrita Arpita Padhy, Kummari Shivani, Ashish Misra, Parul Mishra.
      The aberrant accumulation of misfolded proteins marked by cellular dysfunction and progressive neuronal loss is the hallmark of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. This review examines the pivotal role of ubiquitin modifications in altering the fate of aggregation-prone proteins such as tau, α-synuclein, mutant huntingtin, TAR DNA-binding protein 43 and superoxide dismutase 1. The ubiquitin signatures identified by their linkage types, chain architectures and site specificities emerge as a complex regulatory language that influences the clearance, aggregation or cellular propagation of these aggregating proteins. The dysregulation of other components of the ubiquitin association pathways, such as impaired E3 ligases and deubiquitinases, also contributes to the inefficient protein disposal and disease progression. Understanding how ubiquitin signatures alter the spatiotemporal dynamics of aggregating proteins is critical for advancing our knowledge of disease biology. Here, we focus on the role of ubiquitin modifications and their associated regulators affecting protein fate and neurotoxicity, and highlight the current therapeutic strategies targeting the degradation of aggregating proteins to uncover potential avenues for treating neurodegenerative diseases.
    Keywords:  autophagy; neurodegenerative disease; proteasome; ubiquitin; ubiquitin E3 ligases
    DOI:  https://doi.org/10.1042/EBC20253046
  5. Neurol Clin Pract. 2026 Apr;16(2): e200600
    Approaching Serious Illness Conversations in Amyotrophic Lateral Sclerosis Using Telehealth: A Practical Guide.
    Erica Scirocco, Sabrina Paganoni, Kate Brizzi.
       Purpose of Review: Given the lack of consensus on serious illness conversations (SIC) in amyotrophic lateral sclerosis (ALS) by using telehealth, we aim to provide practical strategies in this setting.
    Recent Findings: Over the past 5 years, there has been substantial growth in telehealth, especially after the global COVID-19 pandemic. In ALS, telehealth has become an increasingly used tool for providing clinical care, especially as the disease progresses, when travel becomes challenging and geographic constraints arise. As ALS advances, clinicians often have SIC with individuals living with ALS and their caregivers using telehealth. In the literature, few recommendations are available to improve telehealth communication in the neuropalliative setting.
    Summary: We present 3 case scenarios showcasing telehealth strategies for SICs, with specific considerations for individuals living with ALS. We provide a strategy, CARE in ALS, to support telehealth communication in individuals with speech impairments. We hope to provide practical guidance for health care clinicians in this specific setting.
    DOI:  https://doi.org/10.1212/CPJ.0000000000200600
  6. FASEB J. 2026 Mar 31. 40(6): e71609
    From Refractory Epilepsy to Neurodegeneration: Emerging Mechanistic and Clinical Insights Into the Ketogenic Diet.
    Chetana Ahire, Rajesh Yadav, Utkarsh U Bhamare, Ginpreet Kaur, Mahesh B Palkar.
      The ketogenic diet (KD), a high-fat, low-carbohydrate intervention, is well established for drug-resistant epilepsy and is increasingly explored in neurodegenerative disorders. KD reduces neuronal hyperexcitability through enhanced γ-aminobutyric acid (GABA)ergic transmission and modulation of neurotransmitter balance, underlying its efficacy in refractory epilepsy. Beyond seizure control, emerging evidence suggests KD may influence disease processes in conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease. Preclinical studies indicate that KD can modulate mitochondrial bioenergetics, oxidative stress, neuroinflammation, neurotransmitter signaling, and gut-brain interactions, though these effects are highly context-dependent and primarily derived from cellular and animal models. Clinical data remain limited, heterogeneous, and short-term, with small cohorts and variable outcome measures. Sustaining adherence and assessing long-term safety remain significant challenges in patient populations. This review summarizes recent experimental and clinical findings, highlighting the molecular and cellular mechanisms through which KD exerts neuroprotective effects. We also evaluate translational evidence and discuss the potential utility of KD as an adjunctive intervention in neurological disease management.
    Keywords:  Alzheimer's disease; Huntington's disease; Parkinson's disease; amyotrophic lateral sclerosis; drug‐resistant epilepsy; ketogenic diet; multiple sclerosis; neurodegeneration
    DOI:  https://doi.org/10.1096/fj.202503317R
  7. FEBS Open Bio. 2026 Mar 19.
    Systemic dysregulation of apolipoproteins in amyotrophic lateral sclerosis serum.
    Finula I Isik, Russell Pickford, Hannah C Timmins, Olivier Piguet, Glenda M Halliday, Matthew C Kiernan, Woojin Scott Kim.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration. Increasing evidence implicates systemic lipid perturbation in ALS pathogenesis. However, the extent and nature of apolipoprotein changes underlying lipid perturbations in ALS remain largely unknown. To address this, we performed a comprehensive analysis of major apolipoproteins involved in lipid metabolism and examined their association with lipoprotein membrane lipids in sporadic ALS (n = 32) and age-matched healthy controls (n = 32), using ELISA and liquid chromatography-mass spectrometry. Compared with controls, serum levels of apoB, apoCI, apoCII, apoCIII and apoE were significantly elevated in ALS, whereas apoAI and apoAII were unchanged. Distributional analyses demonstrated a relative decrease in apoAI and an increase in apoB in ALS, resulting in an elevated apoB/apoAI ratio, a marker of atherogenic risk, alongside a reduced apoAI/apoE ratio. Correlation analyses revealed strengthened interrelationships among apolipoproteins in ALS, suggesting altered regulatory coordination. At the lipid level, phosphatidylcholine (PC) was increased, whereas sphingomyelin (SM) was reduced in ALS serum. Notably, the strong associations of apoB to both PC and SM observed in controls were absent in ALS. Biomarker analyses identified apoE as the strongest discriminator between ALS and control groups. Collectively, these findings demonstrate a coordinated disruption of apolipoproteins and lipoprotein-associated lipids in ALS serum, with likely functional consequences for lipoprotein metabolism. This study provides new insights into lipid dysregulation in ALS pathobiology and supports the emerging view that ALS encompasses not only neurodegenerative processes but also systemic metabolic reprogramming.
    Keywords:  Amyotrophic lateral sclerosis; apoB; apoE; apolipoproteins; lipids; lipoproteins
    DOI:  https://doi.org/10.1002/2211-5463.70232
  8. SLAS Discov. 2026 Mar 14. pii: S2472-5552(26)00009-2. [Epub ahead of print] 100303
    High-throughput screening of ALS patient iPSC-derived spinal motor neurons identifies novel compounds that increase neurofilament light chain expression.
    Gulcan Semra Sahin, Paul J Guyett, Kaiping Xu, Jennifer Kouznetsova, Wei Zheng, Michael Hendrickson.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease primarily affecting motor neurons both in the spinal cord and brain. The cardinal pathology of ALS is motor neuron-selective inclusion of proteins such as TDP43, SOD1, C9orf72-derived dipeptide repeats, or FUS due to the mutations in the genes encoding them. Both familial and sporadic forms of ALS also show neurofilament (NF) aggregates, attributed to an imbalance in subunit expression, particularly a decrease in neurofilament light chain (NF-L) levels. Current FDA-approved treatments extend survival for only a few months, highlighting the urgent need for new therapies. In this study, we developed a cell-based reporter system for high-throughput screening by engineering induced pluripotent stem cells (iPSCs) derived from ALS patients and differentiating them into spinal motor neurons. We screened over 6,000 compounds using these reporter iPSC-derived motor neurons and identified a novel compound that increases NF-L expression by more than 50%. However, this novel compound also inhibits TGF-β signaling, prompting us to optimize its activity through a hit-to-lead chemistry analysis. In our subsequent investigations, we identified an additional compound that does not affect TGF-β signaling and outperforms the original compound in both in vitro and in vivo drug metabolism and pharmacokinetics assays. Our study highlights the utility of iPSC-derived neurons in disease modeling and illustrates how they can be employed to discover new compounds for therapeutic development through extensive screening in disease-relevant settings.
    Keywords:  Amyotrophic lateral sclerosis; drug discovery; drug metabolism and pharmacokinetics; induced pluripotent stem cells, motor neurons, quantitative high throughput screen
    DOI:  https://doi.org/10.1016/j.slasd.2026.100303
  9. Neurosci Lett. 2026 Mar 15. pii: S0304-3940(26)00079-0. [Epub ahead of print]877 138580
    The role of IRF5 in Microglia-Mediated neuroinflammation in ALS.
    Lu Yang, Wenyuan Fan, Zuhuan Wang, Minhua Wu, Yanchun Chen, Jitai Cheng, Fenghua Zhou, Zhangyu Guo.
      The occurrence and development of amyotrophic lateral sclerosis (ALS) involve neuroinflammatory responses, in which microglial activation plays a critical role. IRF5, a key regulator of inflammatory responses, is implicated in the disease mechanisms of various conditions. However, its mechanism in ALS remains unclear. This study found that IRF5 expression was significantly increased in hSOD1-G93A transgenic ALS mice and cell models, primarily localized in activated microglia. Silencing IRF5 altered microglial polarization, suppressed the release of inflammatory factors, enhanced phagocytic function, and reduced motor neuron apoptosis in a co-culture system. Mechanistic studies suggested that IRF5 may regulate microglial function through the NF-κB signaling pathway. This study reveals the key role of IRF5 in microglia-mediated neuroinflammation and neuronal damage in ALS, indicating that targeting IRF5 could represent a promising treatment strategy for this disease.
    Keywords:  Amyotrophic lateral sclerosis; IRF5; Microglia; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.neulet.2026.138580
  10. J Clin Invest. 2026 Mar 16. pii: e199841. [Epub ahead of print]136(6):
    Decoding neurodegeneration one cell at a time.
    Olivia Gautier, Thao P Nguyen, Aaron D Gitler.
      Neurodegenerative diseases are characterized by protein misfolding and the selective vulnerability of specific neuronal subtypes. This selective vulnerability presents a paradox; most neurodegenerative disease genes are expressed broadly throughout the brain, and some ubiquitously, but only certain types of neurons are lost while others are resistant. The molecular basis for selective neuronal vulnerability has remained a mystery, but recent genomics technological innovations are starting to provide mechanistic insights. Here, we review how single-cell genomics techniques - single-cell transcriptomics, single-cell epigenomics, and spatial transcriptomics - advance our molecular understanding of selective vulnerability and neurodegeneration across Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington disease. Together, these approaches reveal the cell types affected in disease, define disease-associated molecular states, nominate candidate determinants of vulnerability and degeneration, and situate degenerating neurons within their local tissue context. Continued development and application of these techniques, including single-cell perturbation screens, will expand descriptive atlases of relevant cell types in health and disease and identify causal mechanisms, revealing the molecular basis of vulnerability and degeneration and informing therapeutic development.
    DOI:  https://doi.org/10.1172/JCI199841
  11. Free Radic Biol Med. 2026 Mar 12. pii: S0891-5849(26)00228-5. [Epub ahead of print]249 469-488
    Aldh3a1-mediated detoxification of reactive aldehydes contributes to distinct muscle responses to amyotrophic lateral sclerosis progression.
    Ang Li, Li Dong, Xuejun Li, Jianxun Yi, Jo-Yu Wu, Jianjie Ma, Jingsong Zhou.
      Different muscles exhibit varied susceptibility to degeneration in Amyotrophic Lateral Sclerosis (ALS), a fatal neuromuscular disorder. Extraocular muscles (EOMs) are particularly resistant to ALS progression, and exploring the underlying molecular nature may offer significant therapeutic value. Reactive aldehyde 4-hydroxynonenal (HNE) is implicated in ALS pathogenesis, and Aldh3a1 is an inactivation-resistant intracellular aldehyde dehydrogenase that detoxifies 4-HNE to protect eyes against UV-induced oxidative stress. We detected prominently higher levels of Aldh3a1 in mouse EOMs compared to other muscles under normal physiological conditions. In an ALS mouse model (hSOD1G93A) reaching end-stage, Aldh3a1 expression was maintained high in EOMs, substantially elevated in soleus and diaphragm, but only moderately increased in extensor digitorum longus (EDL) muscle, which endured the most severe pathological remodeling, as demonstrated by unparalleled upregulation of a denervation marker Ankrd1. Importantly, sciatic nerve transection in wildtype mice further confirmed induced Aldh3a1 and Ankrd1 expression in an inverse manner across muscle types in response to denervation. Mechanistically, whole-muscle RNA-Seq and pharmacological tests indicate that higher basal levels of lipid oxidation and 4-HNE in soleus and diaphragm muscles may render them more susceptible to the induction of certain Nrf2-dependent antioxidant enzymes, including Aldh3a1, under pathological stress relative to the EDL muscle. Additionally, the identification of the myoblast fusion marker Mymk as an EOM signature gene suggests that the spontaneous activation of satellite cells contributes to high levels of Aldh3a1 in EOMs. Functionally, adeno-associated virus-mediated overexpression of Aldh3a1 protected myotubes from 4-HNE-induced DNA fragmentation and plasma membrane leakage. It also restored MG53-mediated membrane repair, highlighting its potential for clinical applications.
    Keywords:  Aldehyde dehydrogenase; Amyotrophic lateral sclerosis; Extraocular muscle; Reactive aldehydes; Sciatic nerve transection; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.037
  12. Neurodegener Dis Manag. 2026 Mar 19. 1-12
    Plasma proteomic trajectories before the onset of neurodegenerative diseases.
    Zhihan Zhang, Rui Fan, Sisi Jing, Shiyi Liu, Linqi Liu, Wenjun Que, Dan Lu, Yaoqi Gan, Fei Xiao.
       BACKGROUND: The study aimed to identify indicative proteins associated with the occurrence and mortality of three neurodegenerative diseases (NDDs) and track the changes of proteins before the onset of NDDs.
    RESEARCH DESIGN AND METHODS: We analyzed plasma proteomic data from UK Biobank. Cox regression analyses were utilized to detect the relationship between plasma proteins and the risk of development and all-cause mortality of Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Predictive models were established based on related proteins using Lasso regression.
    RESULTS: We identified 14 disease-associated proteins for AD, 35 for PD, and one for ALS. The trajectory of plasma proteins before the onset of NDDs was portrayed. Neuroinflammation and the remodeling of the extracellular matrix might be common pathways for NDDs.
    CONCLUSIONS: Our results highlighted that the landscape of plasma protein changes before the onset of NDDs.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; diagnosis; prognosis; proteomics
    DOI:  https://doi.org/10.1080/17582024.2026.2646760
  13. JAMA Neurol. 2026 Mar 16.
    Safety and Efficacy of PrimeC in Amyotrophic Lateral Sclerosis: The PARADIGM Randomized Clinical Trial.
    Merit Cudkowicz, Vivian E Drory, Adriano Chio, Christian Lunetta, Christen Shoesmith, Ruben P A van Eijk, Shiran Salomon-Zimri, Diana Shtossel, Nitai Kerem, Guy Shapira, Noam Shomron, Niva Russek-Blum, Ferenc Tracik, Jeffrey Rosenfeld, Jeremy Shefner.
       Importance: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. PrimeC is a fixed-dose oral combination of celecoxib and ciprofloxacin designed to target ALS-related mechanisms, including neuroinflammation, iron homeostasis, and dysregulated microRNAs.
    Objective: To evaluate the safety, tolerability, and potential efficacy of PrimeC in people living with ALS.
    Design, Setting, and Participants: This was a randomized, double-blind, placebo-controlled, phase 2b trial conducted at 4 ALS referral centers from May 2022 to November 2023 and followed by 12-month open-label extension. Adults with definite or probable ALS and disease duration of 30 months or less were eligible. Of 73 screened, 69 were randomized and 68 were included in the intent-to-treat population.
    Interventions: Participants were randomized 2:1 to receive PrimeC or placebo for 6 months, followed by open-label extension PrimeC for all.
    Main Outcomes and Measures: The primary outcome was safety and tolerability. The prespecified primary biomarker outcome was plasma neuron-derived-exosomal TAR DNA-binding protein 43 (TDP-43) or prostaglandinJ2. Secondary outcomes included change in ALS Functional Rating Scale-Revised (ALSFRS-R) score at 6 and 18 months, survival, and time-to-composite events. Exploratory biomarkers included neurofilament light chains, iron-regulatory proteins, and circulating microRNAs.
    Results: The 68 participants were well balanced in age at entry and sex. In the PrimeC group, the mean (SD) age was 59.1 (9.1) years, and 27 of 45 participants were male. In the placebo group, the mean (SD) age was 55.0 (13.0) years, and 14 of 23 participants were male. PrimeC was well tolerated, with a safety profile comparable to placebo (adverse event rate, 66.7% PrimeC vs 65.2% placebo). Drug-related adverse events were more frequent with PrimeC (20.0% vs 4.3%), mostly mild to moderate, and transient. At month 6, the mean ALSFRS-R difference was 2.23 points between PrimeC and placebo (95% CI, -0.61 to 5.07; P = .12). At month 18, ALSFRS-R scores in participants continuously treated with PrimeC maintained a difference (7.92 points; 95% CI, 2.25 to 13.60; P = .007), with significant bulbar difference (3.18 points; 95% CI, 1.32 to 5.04; P = .001). Continuous treatment was associated with lower risk of ALS complications, including hospitalization, respiratory failure, or death (HR, 0.36; 95% CI, 0.15-0.85; P = .02). In the double-blind period, transferrin levels were preserved with PrimeC (1.90 μmol/L difference; P = .03), the negative ferritin-ALSFRS-R correlation observed in placebo (ρ = -0.50; P = .02) was abolished, and ALS-associated microRNAs were downregulated (log2 fold change: miR-199a-3p, -1.87; false discovery rate [FDR] P = .004; miR-199a-5p, -2.23; FDR P < .001; miR-181a-5p: -1.89; FDR P = .001; miR-181b-5p, -1.62; FDR P = .005). Prespecified neuron-derived exosome TDP-43/PgJ2 analyses will be reported separately following completion of development and analyses.
    Conclusions and Relevance: PrimeC was safe and well tolerated over 18 months. Although not powered for efficacy, functional and biomarker findings support a confirmatory trial.
    Trial Registration: ClinicalTrials.gov Identifier: NCT05357950.
    DOI:  https://doi.org/10.1001/jamaneurol.2026.0230
  14. Front Nutr. 2026 ;13 1713253
    Sarcopenia in amyotrophic lateral sclerosis: a key predictor of respiratory dysfunction and disease progression.
    María Teresa Zarco-Martín, María Carmen Andreo-López, Miriam Soraya Yagui-Beltrán, María Luisa Fernández-Soto.
       Background: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness and respiratory decline. Sarcopenia remains underexplored in terms of prevalence and their relationship with disease progression. We aimed to determine the prevalence of sarcopenia in ALS patients, assess the predictive value of morphofunctional assessment tools for sarcopenia, and explore their relationship with respiratory function and disease progression.
    Methods: A cross-sectional study was conducted with 40 ALS patients at the ALS Multidisciplinary Unit, San Cecilio University Hospital in Granada. Sarcopenia was defined based on the European Working Group of Sarcopenia in Older People 2(EWGSOP2) and malnutrition was diagnosed using GLIM criteria. Morphofunctional status was assessed using: Phase Angle (PA) and body composition by Bioelectrical Impedance Vector Analysis, muscle strength through Handgrip Strength (HGS). Respiratory function was evaluated using Forced Vital Capacity (FVC). Associations between sarcopenia, body composition, respiratory function, and disease severity were analyzed using logistic regression models. Receiver operating characteristic analyses were performed to identify optimal predictive cut-off values.
    Results: Sarcopenia was identified in 25% of ALS patients. Compared with non-sarcopenic individuals, sarcopenic patients exhibited significantly lower muscle mass indices, PA, and HGS, along with higher extracellular water percentage (%ECW). Malnutrition was more frequent in sarcopenia group (90% vs. 25%, p < 0.001). Respiratory impairment was more pronounced in sarcopenic patients, with reduced FVC and elevated pCO₂ (p = 0.02), and a greater need for non-invasive mechanical ventilation (NIMV) (70% vs. 10%, p = 0.001). VC correlated positively with body cell mass index (BCMI) (r = 0.450), skeletal muscle mass index (SMI) (r = 0.413), and ALSFRS-R score (r = 0.731; all p < 0.05). Lower PA, BCMI, and ALSFRS-R scores, together with higher %ECW and partial pressure of carbon dioxide (pCO₂), predicted sarcopenia risk. Reduced BCMI, HGS, Short Physical Performance Battery (SPPB) and sarcopenia were associated with the need of NIMV. BCMI (cut-off:8.05 kg/m2; AUC:0.889) and ALSFRS-R (cut-off:33 points; AUC:0.884) were the most accurate predictors of sarcopenia and ventilatory support, respectively.
    Conclusion: This study is the first to assess sarcopenia prevalence in ALS patients using standardized diagnostic criteria. The findings highlight the relationship between sarcopenia, malnutrition, and respiratory decline. PA, BCMI, and respiratory parameters emerge as potential tools for sarcopenia and NIMV risk stratification.
    Keywords:  amyotrophic lateral sclerosis; disease severity; muscle mass; respiratory decline; sarcopenia
    DOI:  https://doi.org/10.3389/fnut.2026.1713253
  15. EMBO J. 2026 Mar 20.
    ALS mutations disrupt self-association between the ubiquilin STI1 hydrophobic groove and internal placeholder sequences.
    Joan Onwunma, Saeed Binsabaan, Shawn P Allen, Sachini R Thanthirige, Deepika Gaur, Banumathi Sankaran, Matthew L Wohlever.
      Ubiquilins are molecular chaperones that play multifaceted roles in proteostasis, with point mutations in UBQLN2 leading to altered phase-separation properties and amyotrophic lateral sclerosis (ALS). Our mechanistic understanding of this essential process has been hindered by a lack of structural information on the STI1 domain, which is essential for ubiquilin chaperone activity and phase separation. Here, we present the first crystal structure of a ubiquilin-family STI1 domain bound to a transmembrane domain (TMD), and show that ALS mutations disrupt the STI1-TMD interaction. We further demonstrate that ubiquilins contain multiple conserved internal sequences that bind to the STI1 domain, including the PXX-repeat region that is a hotspot for ALS mutations. We propose that these placeholder sequences prevent solvent exposure of the STI1 hydrophobic groove and contribute to the multivalency that drives ubiquilin phase-separation. Together, this work provides a new paradigm for understanding how STI1 domains modulate ubiquilin chaperone activity and phase separation, and offers insights into the molecular basis of ALS pathogenesis.
    Keywords:  Amyotrophic Lateral Sclerosis; Biomolecular Condensates; Membrane Proteins; Proteostasis; Ubiquilins
    DOI:  https://doi.org/10.1038/s44318-026-00745-9
  16. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Mar 17. 1-13
    ALS motor phenotypes: a revised 'OPM' classification.
    Thomas Meyer, Nicola Ticozzi, Markus Weber, John Ravits, Paul Lingor, Magdalena Kuźma-Kozakiewicz, Matthias Boentert, Torsten Grehl, Philippe Corcia, Mónica Povedano Panadés, André Maier, Caroline Ingre, Hakan Cetin, Patrick Weydt, Christian Lunetta, Leonard van den Berg, Albert C Ludolph, David Brenner, Martin R Turner, Angela Genge.
       BACKGROUND: Defining motor phenotypes in amyotrophic lateral sclerosis (ALS) is important for individualized care and optimal therapeutic trial design. The "ALS-OPM" classification is based on the onset region (O), the propagation of motor symptoms (P), and the degree of clinical upper (UMN) and/or lower (LMN) motor neuron dysfunction (M).
    METHODS: An international ALS expert focus group was held in September 2025, followed by a consensus process through which revisions of the OPM classification were finalized.
    RESULTS: Onset (O1-4) identifies first motor symptoms as relating to the head (O1), distal/proximal arm (O2d/p), respiratory/axial trunk (O3r/a), or distal/proximal leg (O4d/p). Onset symptoms are defined by weakness or slowed, poorly coordinated voluntary movements in the muscles of the head, arm, trunk, or leg, including dysarthria, dysphagia, dysphonia, dyspnea, and axial instability. Propagation (P1(n)) or absence of propagation (P0(n)) of motor symptoms from the onset region to another body region are designated, where n denotes the number of months from onset to propagation or assessment. The degree of UMN dysfunction (slowed, poorly coordinated voluntary movements, hyperreflexia and/or spastic muscle tone, emotional lability) and/or LMN dysfunction (weakness with associated muscle atrophy) is classified as follows: balanced UMN and LMN dysfunction (M0); dominant (M1d) or pure UMN dysfunction (M1p); dominant (M2d) or pure LMN dysfunction (M2p); and dissociated UMN/LMN dysfunction (M3), in which the arms and legs predominantly show LMN and UMN involvement, respectively.
    CONCLUSION: The revised ALS-OPM classification aims to make it routine, practical and feasible to capture phenotype in clinical practice and therapeutic trials.
    Keywords:  ALS motor phenotypes; Amyotrophic lateral sclerosis; OPM; classification; revision
    DOI:  https://doi.org/10.1080/21678421.2026.2644277
  17. Ann Neurol. 2026 Mar 19.
    High Prevalence of SOD1 Pathogenic Variants in the UK Biobank: Implications for Early Intervention in Amyotrophic Lateral Sclerosis.
    Delia Gagliardi, Chiara Villella, Matteo Zanovello, Virginia Iacobelli, Stefania Corti, Giacomo Pietro Comi, Pietro Fratta, Henry Houlden, Arianna Tucci, Dario Ronchi.
       OBJECTIVE: SOD1 is the second most frequently mutated gene in European patients with amyotrophic lateral sclerosis (ALS). Given the recent authorization of SOD1-targeted antisense oligonucleotides for SOD1-ALS, prompt screening for SOD1 mutations in patients with ALS patients is highly recommended. Large-scale genomic analysis could inform on the population-based prevalence of SOD1 mutation carriers, who would potentially benefit from treatment. We aim to determine the number of people with pathogenic SOD1 variants in the UK Biobank (UKB), to address a critical gap between clinical and genetic prevalence of SOD1-ALS.
    METHODS: We analyzed SOD1 variants within exome sequencing data from 470,000 individuals aged over 40 years. Pathogenicity was evaluated using referenced databases and American College of Medical Genetics and Genomics (ACMG) guidelines. Leveraging the UKB carrier frequency and age at onset data, we estimated the genetic prevalence of SOD1-ALS. We examined factors that may influence penetrance.
    RESULTS: We identified 122 individuals with monoallelic SOD1 coding variants, 93.4% of whom were asymptomatic. Additionally, the low-penetrance p.Asp91Ala variant was observed in heterozygosis in 535 subjects, whereas it was never found in homozygosis. Excluding this variant, the expected number of people developing SOD1-ALS is 1.04:100,000 in the UK population, 4 times higher than clinically reported figures. Symptomatic carriers had significantly increased levels of serum neurofilament at baseline. Age-related penetrance was higher in non-p.Asp91Ala carriers versus p.Asp91Ala carriers. Long-term survivor status was associated with p.Asp91Ala genotype, older age, and lower neurofilament levels.
    INTERPRETATION: Incomplete and age-related penetrance, along with underascertainment due to disease heterogeneity and limitations in data collection, likely account for the reduced number of symptomatic patients identified. Our findings highlight the need to identify genetic and environmental factors, as well as biological indicators, able to influence disease penetrance and phenoconversion risk in presymptomatic carriers and to predict treatment response in patients. ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78195
  18. Cell Rep Med. 2026 Mar 17. pii: S2666-3791(26)00065-0. [Epub ahead of print]7(3): 102648
    Identification of tofersen PD-response biomarkers in VALOR clinical trial CSF via multiplexed quantitative proteomics.
    Amanda J Guise, Kyle L Ferber, Damon Young, Amanda L Edwards, Somayeh Sabouri, Kyle B Fraser, Eric Milliman, Edward D Plowey, Jad Zoghbi, Stephanie M Fradette, Danielle L Graham.
      Tofersen, the first approved genetically targeted therapy for amyotrophic lateral sclerosis (ALS), demonstrates significant lowering of plasma neurofilament in adults carrying mutations in the superoxide dismutase 1 (SOD1) gene; however, additional biomarkers of treatment response in ALS are lacking. Here, we analyze longitudinally collected cerebrospinal fluid (CSF) samples from the phase 3 VALOR clinical trial to identify candidate tofersen treatment-response biomarkers in SOD1-ALS via quantitative proteomics. We observe significant modulation from baseline abundance for 56 proteins in tofersen-treated participants relative to placebo, including CSF GPNMB, which is significantly and continuously elevated across all post-baseline timepoints. We orthogonally confirm this observation by GPNMB immunoassay in independent tofersen-treated cohorts. Taken together, these data identify pharmacodynamic-response biomarkers of tofersen treatment that can be measured as early as 4 weeks post-treatment in SOD1-ALS patients and demonstrate the utility of leveraging unbiased proteomic screening integrated with targeted validation methods to identify pharmacodynamic-response biomarkers in clinical trial patient samples.
    Keywords:  SOD1-ALS; amyotrophic lateral sclerosis; antisense oligonucleotide therapy; cerebrospinal fluid biomarkers; glycoprotein non-metastatic melanoma protein B; motor neuron disease; neurofilament; pharmacodynamic-response; superoxide dismutase; tofersen
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102648
  19. Drug Deliv. 2026 Dec 31. 33(1): 2645830
    Overcoming the blood‒brain barrier: nanomedicine strategies for targeted delivery and multimodal therapy in Alzheimer's disease.
    Jiahui Li, Liting Guo, Weiyi Cai, Juanjuan Mei, Jie Liu, Yanan Liu.
      Alzheimer's disease (AD) remains a significant therapeutic challenge, primarily because the formidable blood‒brain barrier (BBB), which drastically limits the brain bioavailability of most drugs. Nanoparticle-based drug delivery systems offer a promising strategy to overcome this central obstacle. This review systematically examines the design, mechanisms, and applications of nanomedicine in AD therapy. We analyze key strategies for enhancing BBB penetration through surface engineering and the utilization of various nanocarriers, including liposomes, exosomes, dendrimers, and carbon dots. Furthermore, we discuss how stimuli-responsive release mechanisms (e.g. responsive to pH, enzymes, reactive oxygen species, light, or ultrasound) enable targeted and precise drug delivery. A critical focus is placed on how these multifunctional nanoplatforms can address multiple AD pathogenic pathways simultaneously, such as amyloid-β and tau aggregation, cholinergic dysfunction, oxidative stress, neuroinflammation, and gut‒brain axis dysregulation. Although preclinical evidence is compelling, the clinical translation of these nanotherapies is hindered by challenges related to long-term biocompatibility, scalable manufacturing, patient heterogeneity, and regulatory frameworks. This review highlights the translational potential of nanomedicine in AD treatment while outlining the key hurdles that must be addressed for its successful implementation.
    Keywords:  Alzheimer's disease; amyloid-β; blood–brain barrier; drug delivery; nanomedicine; nanoparticles; reactive oxygen species; tau protein
    DOI:  https://doi.org/10.1080/10717544.2026.2645830
  20. Front Immunol. 2026 ;17 1718318
    Targeting lipocalin-2 for multiple sclerosis: a dual role in diagnosis and therapy.
    Ruqayya Afridi, Won-Ha Lee, Minsoo Song, Kyoungho Suk.
      The discovery of novel biomarkers and therapeutic targets is essential for advancing multiple sclerosis (MS) treatment strategies. Lipocalin-2 (LCN2), a 25-kDa glycoprotein, has gained considerable attention for its diverse roles in immune regulation and neuroinflammation. Its expression varies across MS subtypes and disease stages, influencing both peripheral immune responses and central nervous system pathology. Growing evidence has demonstrated the involvement of LCN2 in modulating immune cell function, glial reactivity, and blood-brain barrier integrity. Clinical studies have consistently correlated LCN2 levels in patient biofluids with disease parameters, supporting its potential as a biomarker. Moreover, experimental studies targeting LCN2 have shown promising therapeutic potential. This review examines the role of LCN2 in MS, focusing on its impact on peripheral immune cells, neuroinflammation, and its viability as a biomarker and therapeutic target. We also discuss the relevance of LCN2-targeting therapies within the evolving MS treatment landscape, underscoring the need for further research in this area.
    Keywords:  biomarker; lipocalin-2; multiple sclerosis; neuroinflammation; therapeutic target
    DOI:  https://doi.org/10.3389/fimmu.2026.1718318
  21. Clin Chem Lab Med. 2026 Mar 13.
    Translating neurofilament light chain testing into clinical practice: a multidisciplinary implementation roadmap.
    Roberto Furlan, Alessia Di Sapio, Diana Ferraro, Elena Rossi, Paola Valentino, Daniela Terracciano.
      Neurofilament light chain (NfL) has been identified as a sensitive and broadly validated biomarker of neuroaxonal injury across multiple neurological conditions, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and atypical parkinsonian syndromes. This position paper provides a multidisciplinary roadmap for translating circulating NfL testing into routine clinical practice, integrating analytical, interpretative, and organizational dimensions. It summarizes the biological basis and clinical evidence supporting NfL as a diagnostic, prognostic, and monitoring tool, emphasizing its high sensitivity to neuroaxonal injury across both acute inflammatory and chronic degenerative processes. Comparative analysis of immunoassay technologies identifies strengths and critical sources of variability, while operational guidelines highlight the need for pre-analytical standardization, inter-laboratory harmonization, and participation in quality control schemes. Confounders such as age, BMI, renal function, and comorbidities are shown to significantly influence interpretation, supporting the use of age-adjusted Z-scores, percentiles, and longitudinal normalization for accurate patient-level evaluation. From a clinical standpoint, the paper focuses on practical indications for NfL testing in MS, recommending its use for disease activity prediction and monitoring, treatment decisions and treatment response assessment. Integration of blood NfL with magnetic resonance imaging (MRI), glial fibrillary acidic protein (GFAP) and other biomarkers measurement is proposed as a core strategy for biomarker-driven precision neurology. The authors outline an implementation model encompassing laboratory validation, structured reporting and alignment with national neurological care pathways. They conclude that the transition of NfL into clinical use requires harmonized analytical procedures, interdisciplinary education, and sustainable governance frameworks. Priority actions include regulatory qualification, establishment of international reference materials, and development of pragmatic real-world trials to consolidate its clinical utility. When these measures are achieved, NfL will represent a cornerstone biomarker for precision neurology and neurodegeneration monitoring.
    Keywords:  biomarker standardization; clinical validation; multiple sclerosis; neurodegeneration; real-world evidence
    DOI:  https://doi.org/10.1515/cclm-2025-1743
  22. Neurol Ther. 2026 Mar 14.
    From Environment to Symptoms: Mapping Premorbid Risk Factors onto Clinical Features of ALS in a Patient-Reported Database in China.
    Xinyu Li, Qianrui Chen, Dongsheng Fan, Lu Chen.
       INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with multifactorial causes, including genetic and environmental factors. This study aimed to identify environmental and lifestyle factors influencing the progression of ALS by leveraging the first and largest patient-reported ALS database in China (the AskHelpU ALS Patient Platform), addressing a critical gap in regional research.
    METHODS: Data from 1421 patients with ALS, including detailed information on occupational exposure, lifestyle habits, dietary patterns, and medical history, were collected from the AskHelpU platform. Statistical analyses were conducted to identify associations between these factors and clinical characteristics. The associations between pre-onset factors and disease progression were analyzed using multicariable generalized linear models, adjusting for multiple comaparisons with the Bonferroni correction.
    RESULTS: Employment in the agriculture industry (p < 0.001) was associated with rapid ALS progression, whereas employment in the leasing and business services industry (p = 0.01) and education industry (p = 0.033) slowed ALS progression. Other key pre-onset prognostic factors were cigarette smoking (p = 0.043) and pre-existing hypertension (p = 0.036).
    CONCLUSION: By utilizing the patient-reported ALS database, this study comprehensively examined the effects of environmental, occupational, and lifestyle factors on ALS progression. These findings provide novel insights into the regional variations in ALS etiology, emphasizing the multifactorial nature of the disease.
    Keywords:  Amyotrophic lateral sclerosis; Dietary patterns; Environmental factors; Lifestyle habits; Occupational exposure
    DOI:  https://doi.org/10.1007/s40120-026-00912-4
  23. Pharmacol Ther. 2026 Mar 13. pii: S0163-7258(26)00052-5. [Epub ahead of print] 109025
    Autophagy-exosome crosstalk in neurodegeneration: Mechanisms and therapeutic opportunities.
    Samin Sedighi, Teng Guan, Federica Michetti, Marco Cordani, Amir Barzegar Behrooz, Farzaneh Sabouni, Mehdi Eshraghi, Ayesha Saleem, Saeid Ghavami, Mohamad-Reza Aghanoori.
      Neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and multiple sclerosis, share a common pathogenic signature: disrupted proteostasis driven by impaired autophagy and maladaptive exosome dynamics. Under normal conditions, autophagy maintains neuronal homeostasis by clearing misfolded proteins and damaged organelles, while exosomes mediate neuroglial communication. When autophagic flux is impaired or lysosomal function is compromised, intracellular cargo handling can shift toward secretion, and undegraded cargo may be redirected into exosomes/EVs, which disseminate pathogenic proteins such as amyloid-β, tau, α-synuclein, and TDP-43, a phenomenon reported in several experimental models and proposed to contribute to intercellular spread of pathology. This dual dysregulation amplifies neuroinflammation, demyelination, and progressive neuronal loss. Pharmacological strategies aimed at restoring the autophagy exosome axis are gaining traction. Agents such as rapamycin and resveratrol enhance autophagic flux, whereas engineered or stem-cell-derived exosomes delivering siRNAs, neurotrophic factors, or anti-inflammatory microRNAs show promise in preclinical neuroprotection and immune modulation. However, translational barriers remain, including safety, biodistribution, dosing, and standardization. Emerging artificial intelligence (AI) and machine learning (ML) frameworks can accelerate translation by integrating multi-omics and exosomal biomarker datasets for early diagnosis, patient stratification, and therapy optimization. Deep learning and generative modeling may further enable rational drug design to fine-tune autophagy and engineer targeted exosome delivery to the brain. Collectively, these advances position the autophagy-exosome axis as an integrative framework linking intracellular clearance with intercellular signaling, with emerging diagnostic and therapeutic implications for neurodegenerative disorders.
    Keywords:  Autophagy: Proteostasis; Biomarkers; Exosomes; Neurodegenerative disorders diagnosis
    DOI:  https://doi.org/10.1016/j.pharmthera.2026.109025
  24. Mol Neurobiol. 2026 Mar 15. pii: 502. [Epub ahead of print]63(1):
    Neuroprotective Effects of the Combination of Green Tea, Saffron, Docosahexaenoic Acid, and α-Lipoic Acid in an In Vitro Model of Parkinson's Disease.
    Rebecca Galla, Simone Mulè, Stefania Battaglia, Valeria Curti, Francesca Romana Ranieri, Francesca Parini, Francesca Uberti.
      Parkinson's disease (PD) is a neurodegenerative disorder characterised by dopamine deficiency and the accumulation of α-synuclein (α-syn), which aggregates into pathological inclusions known as Lewy bodies and Lewy neurites, distributed across multiple brain regions, with a particular prevalence in dopaminergic neurons. Alongside hallmark motor symptoms, PD is often accompanied by non-motor manifestations that severely affect patients' quality of life. Levodopa remains the most effective therapy; however, it is associated with a wide range of side effects and shows little to no efficacy against non-motor symptoms. This study investigates the neuroprotective effects of a combination of four bioactive compounds-green tea, saffron, docosahexaenoic acid (DHA) and α-lipoic acid (ALA)-against the PD-related neurodegeneration. Their ability to cross the blood-brain barrier (BBB) while maintaining its integrity was evaluated using a validated in vitro model. Individual and combined effects of these compounds were assessed on mesencephalic dopaminergic cells exposed to 6-hydroxydopamine (6-OHDA), a widely used in vitro model of PD-like neurotoxicity. The results demonstrated that the combined treatment (Mix) significantly restored cell viability after 6-OHDA exposure and more effectively reduced oxidative and nitrosative stress, as well as lipid peroxidation, compared to single compounds. Furthermore, the Mix markedly decreased the production of pro-inflammatory cytokines (including tumour necrosis factor-alpha (TNF-α) and interleukins) and downregulated the expression of PTEN-induced kinase 1 (PINK1) and Parkin, two key markers of PD-related neurodegeneration. In conclusion, these results indicate that the Mix has a suggest a synergistic-like impact on various disease-causing pathways in PD, highlighting its promise as a multi-faceted neuroprotective approach.
    Keywords:  Docosahexaenoic acid; Green tea; Nutraceutical; Parkinson’s disease; Saffron
    DOI:  https://doi.org/10.1007/s12035-026-05800-4
  25. Exp Neurol. 2026 Mar 15. pii: S0014-4886(26)00091-9. [Epub ahead of print] 115728
    Naturally occurring antibodies against ASC reduced in Alzheimer's disease and alleviating AD-type pathology in APP/PS1 mouse.
    Xiaopeng Zhu, Xia Lai, Juan Deng, Yan Long.
      The disruption or increased permeability of the blood-brain barrier (BBB) results in dysregulated autoantibody profiles in Alzheimer's disease (AD) patients. Naturally occurring antibodies against ASC (NAbs-ASC), which are present in human blood, can block the ability of ASC specks to seed Aβ aggregation. However, the characteristics and functions of NAbs-ASC in AD remain unclear. In this study, we found that plasma levels of NAbs-ASC were reduced in AD patients and showed a negative correlation with the severity of cognitive impairment and with plasma Aβ42/40 ratios. NAbs-ASC treatment reduced Aβ production and attenuated Aβ-induced cytotoxicity in AD cell models. Furthermore, passive immunization with NAbs-ASC or active immunization with ASC peptides improved cognitive function, attenuated Aβ deposition, reduced Tau phosphorylation, inhibited neuroinflammation and apoptosis, and improved synaptic plasticity in APP/PS1 mice. These findings support that NAbs-ASC may be an important physiological protective factor for AD, and that Immunotherapy targeting ASC may be a potential therapeutic intervention for the disease.
    Keywords:  Alzheimer's disease; Autoimmunity; NAbs-ASC; Β-Amyloid
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115728
  26. Neural Regen Res. 2026 Mar 14.
    Identification of novel biomarkers for Alzheimer's disease: A deep learning omics-based approach to drug pair discovery and exploration of potential therapeutic targets.
    Yuying Zhao, Jun Lei, Zixuan Wang, Siyuan Yang, Zhengduo Zhao, Yajun Xie, Jianhua Ran, Guangchao Zang.
       ABSTRACT: The understanding of Alzheimer's disease is shifting from a traditional focus on Aβ/tau pathology to an emerging consensus that positions immune dysregulation as a central synergistic driver in the early stages of the disease. However, the causal relationships between peripheral immune cells, plasma proteins, and Alzheimer's disease, as well as the mediating effects of plasma proteins on the disease, remain poorly understood. Moreover, there are no effective drug combination therapies targeting plasma proteins for Alzheimer's disease. This study investigated the causal associations between immune cells, plasma proteins, and Alzheimer's disease, with a focus on the role of Fc gamma receptor 3A in disease progression. Using a two-sample Mendelian randomization approach, we identified 59 plasma proteins and 65 immune cell types significantly associated with Alzheimer's disease. We performed data mining of a large Alzheimer's disease cohort and drug databases and established a biofactor-regulated neural network for rapidly screening and optimizing compound drug pairs. Among the immune cells, CD8+ T cells, particularly CD8+CD28+CD45RA. T cells, were found to have a protective effect against Alzheimer's disease. Furthermore, increased expression of Fc gamma receptor 3A (also known as CD16a, an activating receptors of NK cells) in plasma and the hippocampus correlated with enhanced CD8+ T-cell infiltration and accelerated Alzheimer's disease progression in 5×FAD mice. Mediation analysis revealed that Fc gamma receptor 3A mediates the effects of CD8+ T cells on Alzheimer's disease risk. Additionally, Fc gamma receptor 3A gene expression levels were significantly higher in patients with Alzheimer's disease compared with individuals with mild cognitive impairment and cognitively normal participants, as revealed by an analysis of the Alzheimer's Disease Neuroimaging Initiative database. These findings suggest that CD8+ T-cell infiltration and Fcγ receptor 3A expression play critical roles in the pathophysiology of Alzheimer's disease and may serve as therapeutic targets. Molecular docking analysis further identified 19 candidate drugs targeting Fcγ receptor 3A. This study proposes novel immune-based therapeutic strategies and introduces an omics-based intelligent drug discovery framework for repurposing existing drugs for the treatment of complex diseases. The key contributions of this study include the identification of potential immune-based therapeutic targets for Alzheimer's disease and demonstration of the utility of bioinformatics and drug repurposing approaches in addressing complex neurodegenerative diseases.
    Keywords:  BFReg-NN; Fcγ receptor 3A; Mendelian randomization; T-cell function; candidate drugs; immune cells; molecular docking; plasma proteins
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00989
  27. Mult Scler Relat Disord. 2026 Feb 10. pii: S2211-0348(26)00102-1. [Epub ahead of print]109 107066
    Targeting Epstein-Barr virus (EBV) for treatment of multiple sclerosis.
    Samantha S Soldan, Troy E Messick, Paul M Lieberman.
      Epstein-Barr Virus (EBV) is now recognized as an essential causal agent in the development of Multiple Sclerosis (MS). MS is a chronic autoimmune disease resulting in demyelination and neurodegeneration in the central nervous system (CNS). EBV is a ubiquitous human γ-herpesvirus that establishes long-term latent infection in a small subpopulation of memory B-lymphocytes. While EBV and B-lymphocytes are known to be drivers of MS autoimmune disease, it remains enigmatic how a small population of EBV-infected cells trigger and drive MS pathogenesis in some individuals. In this review, we discuss the known biology of EBV and its role in MS and other disease, including cancers, where EBV is an essential driving factor in disease progression. We review some of the conditions and cofactors that increase the risk of EBV infection leading to MS and the potential of pharmacological, biologic and vaccine approaches to more selectively target EBV to treat MS.
    Keywords:  EBNA1; Episome; Latency; Multiple Sclerosis; Therapeutics
    DOI:  https://doi.org/10.1016/j.msard.2026.107066
  28. Sci Rep. 2026 Mar 18.
    Implanted brain-computer interface functionality during nighttime in late-stage amyotrophic lateral sclerosis.
    Sacha Leinders, Erik J Aarnoutse, Mariana P Branco, Zac V Freudenburg, Simon H Geukes, Anouck Schippers, Malinda S W Verberne, Max A van den Boom, Benny H van der Vijgh, Nathan E Crone, Timothy Denison, Nick F Ramsey, Mariska J Vansteensel.
      Brain-computer interfaces (BCIs) hold promise as assistive communication technology for people with severe paralysis. Although such BCIs should be available 24/7, feasibility of nocturnal BCI use has not been investigated. Here, we addressed this question using data from an electrocorticography-BCI user with amyotrophic lateral sclerosis. We investigated nocturnal dynamics of neural signal features used for BCI control. Additionally, we assessed nocturnal performance of a decoder trained on daytime data, by quantifying the number of unintentional BCI activations at night. Finally, we developed a nightmode functionality and assessed its performance. Mean and variance of low and high frequency band power were significantly higher at night than during the day. When applied to night data, daytime decoders caused unintentional BCI activations in 100% of nights (245 unintended click-commands and 13 unintended caregiver-calls per hour). The specifically developed nightmode functionality, however, functioned error-free in 79% of nights over a period of ± 1.5 years, allowing the user to reliably call the caregiver. Reliable nighttime use of a BCI requires strategies to adjust to circadian and sleep-related signal changes. This demonstration of a reliable nightmode and its long-term use by an individual with amyotrophic lateral sclerosis underscores the importance of 24/7 BCI reliability.
    Keywords:  Brain-Computer Interface; Circadian; Electrocorticography; Home-use; Night; Sleep
    DOI:  https://doi.org/10.1038/s41598-026-44228-7
  29. Mol Cancer Res. 2026 Mar 19.
    Decoding the biology of the blood-brain tumor barrier in brain cancer.
    Jorge L Jimenez Macias, Philippa Vaughn-Beaucaire, Jingxu Yan, Jasmine Clark, Sean E Lawler.
      Brain cancers are among the most lethal and challenging malignancies to treat in the clinic. An important impediment to effectively treat brain tumors is the blood-brain tumor barrier (BTB), an interface generated between the blood-brain barrier (BBB) and intra-cranial tumors, creating a tumor-permissive perivascular microenvironment. The BTB loses endothelial barrier properties in an heterogeneous manner across the tumor, but continues to impede effective intra-tumoral drug delivery, dramatically decreasing the potential of many anti-neoplastic pharmaceutics. This review will provide a summary of our current understanding of the molecular composition and cellular architecture of the BTB, focusing on glioblastoma and other high-grade gliomas. We will summarize different multi-omic and spatial studies performed with the goal to reveal unknown traits of the brain cancer-associated vasculature and identify molecular targets of therapeutic relevance. Our work aims to consolidate our current understanding of the vasculature in brain tumors, and the insights held regarding its role in brain cancer biology and therapeutic drug delivery.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-25-0908
  30. Front Immunol. 2026 ;17 1776302
    Targeting neuroinflammation: itaconate and mesaconate as therapeutic strategies against H7N7 influenza-associated CNS damage.
    Melanie Ohm, Wei He, Dunja Bruder, Karsten Hiller, Martin Korte, Shirin Hosseini.
       Introduction: Influenza A virus (IAV) infection is primarily associated with respiratory disease; however, accumulating evidence indicates that neurotropic strains can induce central nervous system (CNS) inflammation and contribute to persistent neurological dysfunction. Aberrant immune activation is thought to play a critical role in these outcomes, yet therapeutic approaches that effectively attenuate neuroinflammation while preserving antiviral immunity remain limited. Immunometabolic regulators, including the endogenous metabolite itaconate, have recently emerged as key modulators of innate immune responses, although their contribution to virus-induced CNS pathology remains incompletely understood.
    Methods: In the present study, we investigated whether systemic administration of itaconate or its structural isomer mesaconate modulates neuroinflammatory responses and hippocampal synaptic integrity during infection with the neurotropic IAV strain rSC35M (mouse-adapted A/Seal/Mass/ 1/80, H7N7). Using a murine model, treatment was initiated at the onset of clinical symptoms, and both peripheral and central immune responses were assessed at the peak of disease.
    Results and discussion: Neither itaconate nor mesaconate significantly altered overall disease severity, as assessed by body weight loss, although mesaconate attenuated infection-associated hypothermia. Pulmonary inflammatory responses were largely unaffected by treatment; in contrast, mesaconate selectively reduced IL-1β levels in the brain. At the cellular level, H7N7 infection induced pronounced microglial activation within hippocampal subregions, characterized by increased cell density and soma volume, altered process complexity, and enhanced engulfment of postsynaptic material. These infection-induced microglial alterations were partially prevented by mesaconate treatment and largely abrogated by itaconate treatment. Notably, attenuation of microglial density and reactivity during the acute phase was associated with long-term preservation of hippocampal synaptic plasticity. Collectively, these findings indicate that therapeutic administration of itaconate and mesaconate, potentially through distinct mechanisms, can modulate microglia-driven synaptic pathology during neurotropic IAV infection. Targeting immunometabolic pathways may therefore represent a promising strategy to prevent persistent neurological sequelae associated with viral disease.
    Keywords:  hippocampus; influenza A virus infection; metabolites; microglia; synaptic plasticity
    DOI:  https://doi.org/10.3389/fimmu.2026.1776302
  31. Cell Rep Med. 2026 Mar 17. pii: S2666-3791(26)00102-3. [Epub ahead of print]7(3): 102685
    Blood-brain barrier-penetrative lipid nanoparticles enable systemic delivery of TRIM11 mRNA to disaggregate Tau in Alzheimer's disease models.
    Yan Zou, Yujing Sang, Meng Zheng, Bingyang Shi.
      Hyperphosphorylated Tau aggregates are a central pathological hallmark of Alzheimer's disease (AD), yet no approved therapy directly targets this process. mRNA therapeutics provide a transient and non-viral option but are limited by the blood-brain barrier (BBB). TRIM11 is an ATP-independent disaggregase that dissolves pathological Tau fibrils and promotes proteasomal clearance. Here, a ligand-free lipid nanoparticle (PLNP) is developed with zwitterionic, acetylcholine-mimetic poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) as a core component and leverages interactions with nAChRs and chTs to enable BBB transcytosis. Systemic PLNP delivery of TRIM11 mRNA yields an 8.1-fold increase in hippocampal accumulation and >30-fold higher neuronal transfection than unformulated mRNA. In 3×Tg-AD mice, PLNP-mTRIM11 reduces P-Ser396- and AT8-positive Tau aggregates, attenuates neuroinflammation, restores synaptic/neuronal integrity, and improves cognition and nest building for ≥3 months. Early prophylactic dosing prevents Tau pathology and preserves cognitive function, supporting PLNP-mTRIM11 for tauopathy therapy.
    Keywords:  Alzheimer’s disease therapy; BBB-targeted mRNA delivery; PLNP; PMPC lipid nanoparticle; TRIM11 mRNA; Tau aggregates degradation
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102685
  32. Front Microbiol. 2026 ;17 1760096
    How gut microbiota contribute to neuropsychiatric disorders: evidence from neuroimaging studies.
    Chunlan Jia, Wenjie Zhu, Yanling Yuan, Qinglian Xie.
      The interaction between the gut microbiota and central nervous system (CNS) diseases has emerged as a major focus in neuroscience and microbiome research. Accumulating evidence shows that gut microbiota influence the pathogenesis of neurodevelopmental, neurodegenerative, autoimmune, and psychiatric conditions via the microbiota-gut-brain axis. However, the underlying mechanisms are complex and not yet fully elucidated. Advances in multimodal magnetic resonance imaging, positron emission tomography, and diffusion tensor imaging, now enable in vivo visualization of associations between gut microbial alterations and abnormalities in brain structure and function, providing new perspectives for understanding the role of gut microbiota in CNS pathology. This review systematically reviews neuroimaging-based research linking gut microbiota to neurological diseases (e.g., Alzheimer's disease, multiple sclerosis, traumatic brain injury), and psychiatric disorders (e.g., schizophrenia, and autism spectrum disorder). It highlights the mediating roles of microbial metabolites, immune-inflammatory responses, and neuroimmune pathways, and discusses future directions integrating multi-omics data with neuroimaging technologies, as well as their potential clinical applications. What distinguishes this review from its predecessors in the same field is its explicit neuroimaging-driven framework rather than general mechanistic discussion.
    Keywords:  Alzheimer’s disease; autism spectrum disorder; central nervous system diseases; depression; gut microbiota; microbiota-gut-brain axis; multiple sclerosis; neuroimaging
    DOI:  https://doi.org/10.3389/fmicb.2026.1760096
  33. Front Neurosci. 2026 ;20 1768545
    The delivery challenge of adeno-associated virus vector-based gene therapies for neurological diseases.
    Alissa Pak, Darcy Wear, Nareh Tahmasian, Jung Yeon Min, Davina Premraj, Rachel Gibbs, Kiah Spencer, Susanna Fang, Thomas Zerbes, Medha Krishnan, Zahra Nasser, Gerold Schmitt-Ulms.
      There is great anticipation that gene therapies can offer solutions to many neurological diseases. Already, much is known about therapeutic targets and how they would need to be manipulated to mitigate disease. For such gene therapies to move to the clinic, potent CNS delivery vehicles are needed. One line of investigation focuses on adeno-associated viruses (AAV) to address this need. In particular, blood-brain barrier (BBB)-penetrant AAV capsids are of interest due to the relative ease of their intravenous administration. This review will introduce this topic and provide an update on recent developments. First, we describe the physical barriers that must be overcome for AAV-delivered gene therapies to reach target cells in the CNS. We then put a spotlight on the natural AAV9 capsid's inherent propensity to cross the BBB and key lessons learned from its use for delivering a therapeutic payload for the treatment of spinal muscular atrophy. Next, we summarize methods for engineering recombinant AAV (rAAV) capsids with improved brain penetrance, and present in vitro paradigms for predicting their capacity to cross the human BBB. We also present strategies for side-stepping the delivery limitations of existing rAAV vectors. Finally, we point toward a few notable clinical studies whose outcomes may advance our understanding of what rAAV-delivered gene therapies can offer to people afflicted with CNS disorders.
    Keywords:  adeno-associated virus (AAV); capsid; gene therapy (GT); neurodegenerative diseases; neurological disease
    DOI:  https://doi.org/10.3389/fnins.2026.1768545
  34. Front Immunol. 2026 ;17 1762637
    Circulating Toll-like receptor and cytokine profiles and genetic polymorphisms in a Chinese sepsis cohort: potential links to neuroinflammation and blood-brain barrier dysfunction.
    Wu Fan, Rongfen Zhao, Jiaye Liu, Ruixiang Luo, Yun Chen.
       Background: Sepsis is characterised by a dysregulated host response to infection and remains a major cause of morbidity and mortality. Toll-like receptor (TLR)-mediated inflammatory signalling can amplify systemic cytokine release and has been implicated in sepsis-associated brain dysfunction through neuroinflammation and blood-brain barrier (BBB) impairment. This study examined circulating TLR/cytokine profiles and common genetic polymorphisms in key inflammatory genes in patients with sepsis.
    Methods: In this hospital-based case-control study, 480 adult patients with sepsis admitted to the intensive care unit and 840 age- and sex-matched healthy controls were enrolled. Serum levels of TLR2, TLR4, TLR9, IL-1β, IL-6, IL-8, IL-10, TNF-α and IFN-γ were quantified by enzyme-linked immunosorbent assay at the time of sepsis diagnosis. Genotypes of candidate polymorphisms in TLR and cytokine-related genes were determined using a classical polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. Hardy-Weinberg equilibrium was evaluated in the control group. Associations between polymorphisms and sepsis susceptibility were assessed using multivariable logistic regression adjusted for age and sex, and p values were interpreted with consideration of multiple comparisons, including conservative Bonferroni correction in sensitivity analyses.
    Results: Compared with controls, patients with sepsis exhibited significantly higher serum levels of TLR2, TLR4, TLR9, IL-1β, IL-6, IL-8, IL-10 and TNF-α (all p < 0.05), whereas IFN-γ levels were not significantly different. Several polymorphisms were associated with increased sepsis risk, including TLR2 -196 to -174 del, TLR4 rs1927911, TLR9 rs352140, TLR9 rs574836, IL-1B +3954 C/T, IL-6 -174 G/C, IL-10 -1082 G/A, IL-10 -819 T/C, TNF-α -308 G/A and IFN-γ +874 A/T (all p < 0.05), and a subset of these associations remained statistically significant after conservative correction for multiple testing.
    Conclusion: Circulating up-regulation of the TLR-cytokine axis and susceptibility-associated polymorphisms in TLR and cytokine genes support a genetic-inflammatory framework for sepsis in this Chinese cohort, with potential relevance to pathways implicated in sepsis-related neuroinflammation and BBB dysfunction. Because central nervous system involvement and BBB integrity were not directly measured in this study, these links should be regarded as inferential. The present findings motivate further studies incorporating direct central nervous system and BBB endpoints and external validation cohorts, and may inform future biomarker-guided risk stratification strategies.
    Keywords:  PCR–RFLP; Toll-Like receptors; blood–brain barrier dysfunction; cytokines; genetic polymorphism; neuroinflammation; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2026.1762637
  35. Colloids Surf B Biointerfaces. 2026 Mar 12. pii: S0927-7765(26)00200-6. [Epub ahead of print]263 115612
    Recent advances in polymeric nanoparticle-mediated drug delivery system across the blood-brain barrier in Alzheimer's disease.
    Manickam Rajkumar, Dharmalingam Kirubakaran, Prabha Govindaraj, Alagarsamy Shanmugarathinam, Paramasivam Deepak, Prabhakaran Rajkumar, Deenathayalan Uvarajan, V V Sathibabu Uddandrao, Rajendran Manikandan, Pandiyan Balamurugan.
      Alzheimer's disease (AD) is driven by complex and interrelated pathological processes, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, mitochondrial dysfunction, synaptic loss, and chronic neuroinflammation. These multifactorial mechanisms contribute to progressive cognitive decline and limit the effectiveness of conventional therapeutic strategies. Polymeric nanoparticles (PNPs) have emerged as a promising nanotechnological platform for targeted drug delivery in AD, addressing key challenges such as inadequate blood-brain barrier (BBB) permeability, rapid enzymatic degradation of therapeutic molecules, and poor pharmacokinetics. PNPs improve therapeutic efficacy by enabling controlled and sustained drug release, enhancing molecular stability, and promoting selective accumulation in affected brain regions. PNPs can modulate multiple molecular events that underlie AD pathogenesis. They inhibit Aβ fibrillation, reduce tau phosphorylation, scavenge reactive oxygen species (ROS), suppress neuroinflammatory signalling, activate Nrf2-driven antioxidant defense, and regulate microglial polarization toward a neuroprotective phenotype. Additionally, PNPs provide an efficient delivery system for diverse therapeutic agents, including small molecules, peptides, antioxidants, nucleic acids, and natural compounds, which often face challenges in BBB penetration and systemic stability. Recent innovations in surface engineering, biodegradable polymer chemistry, gene-responsive nanocarriers, and stimuli-responsive release systems have further enhanced the potential of PNPs as disease-modifying interventions. Despite these significant advancements, key limitations remain, including uncertainties regarding long-term biosafety, inconsistent biodistribution, challenges in nanoparticle clearance, and translational gaps between preclinical models and humans with AD. Addressing these issues will require interdisciplinary collaboration among materials science, neurobiology, pharmaceutical technology, and clinical research. Overall, this review highlights recent progress, therapeutic mechanisms, and the growing promise of PNP-based brain-targeted nanomedicine as a transformative approach for AD treatment.
    Keywords:  Alzheimer’s disease; Amyloid-β aggregation; Blood–brain barrier; Brain-targeted nanomedicine; Polymeric nanoparticles
    DOI:  https://doi.org/10.1016/j.colsurfb.2026.115612
  36. Neural Regen Res. 2026 Mar 14.
    Multiple sclerosis synaptic connectome: Insights from fluid biomarkers.
    Lorenzo Gaetani, Laura Bellingacci, Silvia Sperandei, Massimiliano Di Filippo.
       ABSTRACT: Multiple sclerosis is a chronic immune-mediated and degenerative disease of the central nervous system. Increasing evidence highlights the role of brain network disconnection in the pathogenesis of clinical progression and irreversible disability accumulation in people with multiple sclerosis. Several pathologic changes contribute to multiple sclerosis-related disconnection, ranging from focal areas of demyelination and axonal transection to atrophy of both cortical and subcortical gray matter structures. In the last years, increasing evidence also suggests a prominent role of synaptic dysfunction in determining brain connectome changes in multiple sclerosis, but objective measures of such alterations are still lacking. In this scenario, the evolving landscape of fluid biomarkers might help to provide the first data on synaptic integrity in multiple sclerosis, as already investigated in primary neurodegenerative diseases, where research has led to the identification of synaptic proteins measurable in cerebrospinal fluid and blood. This review explores the relevance of synaptic dysfunction and loss in multiple sclerosis, as mirrored by synaptic proteins that may serve as fluid biomarker, with specific attention given to presynaptic markers (such as SNAP-25, VAMP-2, and β-synuclein), postsynaptic proteins (such as neurogranin and NPTX2), and astrocyte-derived proteins. The encouraging findings obtained to date, as well as ongoing methodological challenges, will be discussed, together with a proposal for future directions of research in the field, with regard to the need of defining the temporal dynamics of these markers and their relationship with neuroinflammatory and neurodegenerative processes.
    Keywords:  SNAP-25; beta synuclein; biomarkers; blood; cerebrospinal fluid; extracellular vesicles; fluid; multiple sclerosis; neurogranin; plasma; serum; synaptic
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01172
  37. Int J Pharm. 2026 Mar 14. pii: S0378-5173(26)00226-7. [Epub ahead of print]695 126778
    A dynamic in vitro model of blood-brain barrier: effect of different polymeric nanoparticles on the crossing ability.
    Teresa Barra, Marco Bellotti, Michele Conti, Ferdinando Auricchio, Alessandro Caimi, Mariarosaria Vestiti, Enrica Chiesa, Salvatore Valiante.
      The blood-brain barrier (BBB) remains a critical bottleneck for  Central Nervous System (CNS)  drug delivery. While polymeric nanoparticles (NPs) are promising carriers, their development requires advanced screening platforms. This work focuses on the development and validation of a dynamic in vitro BBB model for testing future nanotherapeutics, rather than proposing a specific optimized nanosystem. Although simplified compared to in vivo conditions, this model enables controlled evaluation of endothelial permeability and transport dynamics. By incorporating flow conditions, we investigated how shear stress influences the translocation of PLGA and chitosan NPs, selected for their well-documented contrasting properties. Results show that the fluid-dynamic environment effectively discriminates NPs permeability without toxicity, highlighting the role of surface charge and polymer nature. This study establishes a versatile tool for the standardized evaluation of brain-targeted delivery.
    Keywords:  Blood-brain barrier; Chitosan; PLGA
    DOI:  https://doi.org/10.1016/j.ijpharm.2026.126778
  38. Disabil Rehabil. 2026 Mar 19. 1-17
    Identifying priorities for a national motor neurone disease (amyotrophic lateral sclerosis) guideline: results from an Australian online survey.
    Anna Fragkoudi, Cindy Stern, Danielle Pollock, Timothy Hugh Barker, Ines Semendric, Julie Labra, Steve Vucic, Jo Whitehouse, Zachary Munn.
       PURPOSE: To identify the priorities of people living with motor neurone disease (MND), their carers, asymptomatic genetic carriers, and healthcare professionals (HCPs) in Australia, to inform the development of a national MND care guideline.
    METHODS: An anonymous online survey was distributed via MND organisations and groups to the Australian MND community.
    RESULTS: Two hundred and fourteen individuals completed the survey. Of those, 44.8% (n = 96) were HCPs, with the remaining consisting of people living with MND, genetic carriers, and carers. The following areas were rated as extremely important and should be included in the guideline: diagnosis, service delivery models, clinical care management, caregiver support, and palliative care; while views on genetic testing and cognitive assessment were mixed. Participants highlighted a need for holistic care which considered emotional/psychological and physical aspects of MND. People with MND and their carers want the Australian MND care guideline to highlight proactive and coordinated support prioritising quality of life, while maintaining independence for as long as possible.
    CONCLUSIONS: Identifying priorities is a fundamental step that will shape the forthcoming Australian MND care guideline. This methodology ensures the voices of those with lived experience and interest holders are incorporated from the outset.
    Keywords:  Motor neurone disease; amyotrophic lateral sclerosis; guideline; online survey; priorities
    DOI:  https://doi.org/10.1080/09638288.2026.2643544
  39. bioRxiv. 2026 Mar 04. pii: 2026.03.02.709098. [Epub ahead of print]
    Synergy Feedback Control Predicts Walking Across Multiple Cycles.
    Spencer Williams, Geng Li, B J Fregly.
      Neural feedback is important for healthy control of movement, and multiple neurological disorders (e.g., stroke, cerebral palsy, Parkinson's disease, incomplete spinal cord injury) can be described by how they impair healthy feedback or induce unhealthy feedback. Researchers have created numerous computational neuromusculoskeletal models controlled by simulated neural feedback mechanisms, but these models rarely represent actual human subjects and thus have not found practical application in treating patients with movement impairments. As a step toward designing patient-specific treatments for individuals with neurological disorders, this study used the Neuromusculoskeletal Modeling Pipeline to develop and evaluate a novel synergy-based feedforward (FF)+feedback (FB) model using a personalized, three-dimensional neuromusculoskeletal walking model of an actual human subject post-stroke. Experimental walking data collected from the subject were used to create the subject's personalized walking model. This model was used to calculate lower body muscle activations consistent with the subject's electromyographic, joint motion, and ground reaction data for 5 calibration walking cycles. Nominal FF synergy controls were calculated by averaging the muscle synergies that closely reconstructed the 5 cycles of muscle activations and associated joint moments simultaneously. These nominal FF controls were then scaled by 0, 25, 50, 75, 100, and 125%, and the gap in reproducing individual cycle muscle activations was filled by fitting FB synergy controls as a function of joint positions, velocities, and moments as surrogates for muscle lengths, muscle velocities, and tendon forces. Finally, the six synergy-based FF+FB models controlled the subject's personalized walking model in predictive simulations performed for 3 testing walking cycles withheld from calibration. The 100% FF model (which still had minimal FB) reproduced the testing walking cycles the most closely, and only the 75%, 100%, and 125% FF models generated near-periodic walking motions using initial conditions consistent with experimental values. The 0, 25, and 50% FF models could generate near-periodic walking motions only when the initial conditions were allowed to diverge substantially from experimental values. Our findings suggest that predictive simulations of walking using real experimental data may require a minimum level of feedforward control and sufficient fitting data to predict a subject's actual dynamically consistent motion.
    Keywords:  EMG-driven modeling; Model Personalization; Muscle synergies; Neural feedback; Neuromusculoskeletal modeling; Predictive simulation; Stroke; Treatment Optimization
    DOI:  https://doi.org/10.64898/2026.03.02.709098
  40. Neural Regen Res. 2026 Mar 14.
    Metabolic-based therapeutic strategies to treat Huntington's disease.
    Mariana Coelho Moraes, Muhammad Olanrewaju Buhari, Luciene Bruno Vieira, Fabiola Mara Ribeiro.
       ABSTRACT: Huntington's disease is an autosomal dominant neurodegenerative disorder marked by progressive motor, cognitive, and psychiatric decline. Huntington's disease arises from the expansion of particular DNA sequences (cytosine/ adenosine/guanine repeats that encode glutamine) within the huntingtin (HTT) gene. This expansion leads to the synthesis of a mutant huntingtin protein (mhtt) featuring an excessively long polyglutamine segment, which is harmful and prone to form aggregates or clusters within cells. A range of abnormalities has been observed in both the central nervous system and peripheral tissues as a consequence of mhtt. These include inhibition in autophagy, mitochondrial dysfunction leading to metabolic deficiencies, immune system dysregulation, metabolic alterations, skeletal muscle deterioration, heart failure, testicular shrinkage, and bone density loss. Additionally, mhtt has been implicated in altering lipid metabolism pathways, leading to an increase in lipid accumulation, especially within neuronal cells. This lipid accumulation contributes significantly to cellular toxicity and dysfunction, further exacerbating the neurodegeneration seen in Huntington's disease. Although most studies have focused on neurological, behavioral, motor, and cognitive changes associated with Huntington's disease, several studies have reported changes in proteins, nucleic acids, lipids, and carbohydrate metabolism, which may lead to an anomalous molecular energy profile in individuals with Huntington's disease. This review will focus on understanding how metabolic changes may contribute to central alterations in Huntington's disease by analyzing preclinical and clinical evidence. Additionally, it will explore potential pathways that could be targeted to develop more effective treatments for Huntington's disease.
    Keywords:  Huntington’s disease; bioenergetic deficits; metabolic dysfunction; mitochondrial impairment; neurodegeneration
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01573
  41. Alzheimers Dement. 2026 Mar;22(3): e71263
    Measuring blood-brain barrier dysfunction: a critical appraisal of fluid biomarkers, in vitro models, in vivo imaging, and post-mortem approaches.
    Shakira A van der Panne, Helena Durrant, Jannis F Heuer, Ivana Kancheva, Arno Stellingwerf, Lieuwe T K M Verkaar, Damon Verstappen, Pascalle Mossel, Walter H Backes, Erik N T P Bakker, Jurgen A H R Claassen, Marcel M Verbeek, Louise van der Weerd, Matthias J P van Osch, Helga E de Vries.
      The blood-brain barrier (BBB) maintains central nervous system homeostasis by regulating molecular exchange between blood and brain. BBB dysfunction is associated with aging and neurological disorders such as Alzheimer's disease, stroke, and multiple sclerosis. Diverse approaches are used to study BBB structure and function, including cell-based models, imaging techniques, and fluid biomarkers. While each method has distinct strengths, inherent limitations complicate interpretation and limit comparability across studies. In addition, many methods require specialized expertise, hindering the interdisciplinary integration of findings. This review outlines commonly used methods to assess BBB dysfunction and critically evaluates their relevance, advantages, and drawbacks. It provides guidance for selecting suitable techniques, proposes guidelines, and highlights key challenges in data interpretation. Finally, the review emphasizes the need to clearly define the specific BBB aspect under investigation, calls for standardized protocols, and encourages combining approaches to improve research quality and translation into clinically meaningful insights and applications.
    Keywords:  BBB dysfunction; blood–brain barrier; brain endothelium; critical appraisal; imaging; methods; review
    DOI:  https://doi.org/10.1002/alz.71263
  42. CNS Neurol Disord Drug Targets. 2026 Mar 12.
    Pharmacological Breakthroughs with Extracellular Vesicles-Based Nanomedicine: A Targeted Strategy to Cross the Blood-Brain Barrier in Alzheimer's Disease.
    Jasmeen Kaur, Dushyant, Smita Narwal, Gurvirender Singh, Rupa Devi, Tavleen Kaur, Nisha Grewal, Ashwani K Dhingra.
      Alzheimer's Disease (AD) is a disabling neurodegenerative illness characterized by Amyloid-beta (Aβ) plaque deposition, tau tangles, and neuroinflammation. These pathological characteristics lead to progressive cognitive decline, and drug therapeutic approaches are bedeviled by extreme difficulty with the Blood-Brain Barrier (BBB) that prevents most drugs from effectively crossing into the brain. Extracellular vesicle-based nanomedicine is a prospective approach to overcome this hurdle. Extracellular vesicles are endogenously derived extracellular vesicles that can cross the BBB and deliver a variety of therapeutic cargos, including small interfering RNAs (siRNAs), microRNAs (miRNAs), proteins, and other small molecules. Since they can cross the BBB and exhibit low immunogenicity and toxicity, extracellular vesicles represent a promising strategy for drug delivery against AD. Recent studies have highlighted the potential of extracellular vesiclebased treatments to deliver anti-amyloid and anti-tau therapies, neuroprotectants (e.g., antioxidants), and immune-modulatory factors. Engineered extracellular vesicles containing siRNA against βsecretase eta-site app cleaving enzyme 1 (BACE1), anti-tau oligonucleotides, and anti-inflammatory cytokines have shown promising preclinical efficacy by reducing Aβ deposition, tau aggregation, and neuroinflammation. These changes have been associated with enhanced cognitive function. Besides, extracellular vesicle-based systems were investigated for gene-editing therapeutics with Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 (CRISPR/ Cas9) and Antisense Oligonucleotides (ASOs). Besides scalability concerns, cargo-loading efficiency, and long-term toxicity, extracellular vesicle-based nanomedicine is an innovative platform for targeted drug deli.
    Keywords:  Alzheimer's disease; amyloid-beta; blood-brain barrier; nanomedicine; neuroprotective molecules; therapies.
    DOI:  https://doi.org/10.2174/0118715273418647251208093957
  43. Crit Rev Food Sci Nutr. 2026 Mar 19. 1-18
    The relationship between dietary patterns and neuroinflammation.
    Alessandro Medoro, Giovanni Scapagnini, Frank B Hu, Sergio Davinelli.
      Dietary patterns are now recognized as key modulators of immunometabolic balance, exerting significant effects on the central nervous system (CNS) by regulating immune responses and inflammatory stress. The quality, composition, and timing of nutrient intake shape immune responses, influence glial activity, and alter the vulnerability of the CNS to inflammatory processes. Persistent neuroinflammation, driven by microglial activation, chronic release of pro-inflammatory mediators, and recruitment of peripheral immune cells, is increasingly recognized as a common mechanism underlying a wide range of neurological and psychiatric disorders, from Alzheimer's disease to major depression, reducing the patients' quality of life. The transition from evolutionarily adapted diets, rich in fiber, micronutrients, and unprocessed foods, to Western dietary patterns characterized by excess saturated fats, refined sugars, and ultra-processed products has significantly disrupted systemic and neuroimmune homeostasis. These nutritional changes contribute to a pro-inflammatory brain environment both directly, through the immunomodulatory effects of dietary components and metabolites, and indirectly, through increased intestinal permeability, dysbiosis, and activation of peripheral inflammatory cascades. Conversely, nutritional strategies such as plant-based, low-fat, low-carbohydrate, Dietary Approaches to Stop Hypertension (DASH), Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND), and time-restricted diets appear to counteract these detrimental effects. Preclinical and early clinical evidence suggests that these approaches reduce microgliosis, inhibit inflammasome signaling, lower systemic inflammation, and reshape the gut microbiota to promote anti-inflammatory metabolites and better gut-brain communication. Although large-scale clinical validation is still needed, shifting dietary patterns from pro-inflammatory to neuroprotective profiles offers a feasible and promising approach to reduce neuroinflammation and support brain health.
    Keywords:  DASH and MIND diets; Western diet; low-fat and low-carbohydrate diets; neuroinflammation; plant-based diet; time-restricted diets
    DOI:  https://doi.org/10.1080/10408398.2026.2645262
  44. Exp Neurol. 2026 Mar 18. pii: S0014-4886(26)00102-0. [Epub ahead of print] 115739
    TREM2 as a possible link between Alzheimer's disease and diabetes mellitus.
    Wendan Chen, Nanqu Huang, Wendi Huang, Mei Wang, Yong Luo, Juan Huang.
      Alzheimer's disease (AD) and diabetes mellitus (DM) represent escalating global health burdens, with epidemiological and clinical studies demonstrating a strong association between them. Diabetic patients face a significantly increased risk of AD, and poor glycemic control can accelerate AD progression. Chronic low-grade inflammation is increasingly recognized as a central mechanism bridging the two diseases. Triggering receptor expressed on myeloid cells 2 (TREM2), a key immune regulator, has emerged as a critical player in both AD and DM. In AD, TREM2 is specifically expressed on microglia, mediating neuroinflammatory and neurodegenerative processes while regulating both amyloid-β (Aβ) and Tau pathology. In DM, TREM2 contributes to insulin resistance and metabolic dysregulation. Genetic variants of TREM2 are established risk factors for AD, while altered TREM2 expression correlates with DM pathology. This review summarizes TREM2's structural and functional characteristics, its dual roles in AD and DM, and its potential as a therapeutic target. Elucidating these shared TREM2-mediated mechanisms may provide novel insights into the pathological interplay between AD and DM and inform precision therapeutic strategies.
    Keywords:  Alzheimer's disease; Diabetes mellitus; Insulin resistance; Microglia; Neuroinflammation; TREM2
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115739
  45. Expert Opin Drug Discov. 2026 Mar 16.
    The futility of the familiar: rethinking strategies for the development of small molecules for neurodegenerative disorders.
    Manuel Novas, Maria João Matos, Christina Li Lin Chai.
       INTRODUCTION: As life expectancy increases globally, the prevalence of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases continues to rise. Despite decades of intensive research and substantial investment, effective preventive or curative treatments remain unavailable. Much of the drug discovery efforts have focused on small-molecule therapeutics. However, these approaches have yielded limited clinical success. This lack of progress underscores the inherent complexity of neurodegenerative diseases and suggests that conventional drug discovery paradigms may be overly simplistic or fundamentally flawed.
    AREAS COVERED: In this article, the authors explore the key challenges underlying the failure of small-molecule strategies in neurodegenerative research and discuss emerging avenues that may offer more promising therapeutic outcomes for brain disorders.
    EXPERT OPINION: Conventional approaches in CNS drug discovery and development have not yielded disease-modifying CNS drugs. To be successful, it is important to rethink strategies, assays, animal models from scratch and redesign how R&D in CNS diseases should be carried out.
    Keywords:  Neurodegenerative diseases; blood brain barrier; in vitro and in vivo assays; neuroinflammation; neuroprotection; oxidative stress; paradigm shifts; small molecules
    DOI:  https://doi.org/10.1080/17460441.2026.2646603
  46. CNS Neurol Disord Drug Targets. 2026 Mar 10.
    Breaking Barriers: Advanced Pharmacological Mediators for Neuropsychiatric Disorders.
    Tapas Kumar Mohapatra, Atul R Bendale, Tara Shankar Basuri, Prashant Tiwari, Sunil Kumar Kadiri, Pradeep Kumar Samal.
      Neuropsychiatric disorders include bipolar disorder, schizophrenia, and major depression. They present significant challenges to clinical management due to their complex pathophysiology and diverse symptomatology. Despite advancements in psychopharmacology, existing treatments often exhibit partial efficacy, variable patient responses, and substantial side effect profiles, which underscores the need for novel therapeutic strategies. This review provides a comprehensive examination of recent breakthroughs in the design, expansion, and delivery of pharmacological mediators intended for improving the management of neuropsychiatric disorders. We explore cutting-edge drug-delivery systems, such as liposomes, nanoparticles, and polymeric micelles, which enhance drug bioavailability and targetability, thereby facilitating more effective crossing of the blood-brain barrier. The integration of nanotechnology-based approaches and ligand-targeted delivery systems has shown promise in optimizing therapeutic concentrations within the central nervous system while minimizing systemic toxicity. Advances in prodrug formulations and carrier-mediated transport mechanisms are discussed as innovative strategies to improve drug solubility, absorption, and sustained release. This review also underscores the potential of personalized medicine and biomarkerdriven approaches in customizing treatment regimens to individual patient profiles, thereby enhancing therapeutic efficacy and clinical outcomes. These innovations in drug design and delivery hold significant promise for revolutionizing the treatment landscape of neuropsychiatric disorders, offering hope for improved patient care and quality of life.
    Keywords:  Neuropsychiatric disorders; blood-brain barrier; drug delivery systems; nanotechnology; personalized medicine; pharmacological mediators.
    DOI:  https://doi.org/10.2174/0118715273401761251111071404
  47. Drug Des Devel Ther. 2026 ;20 585486
    Baicalin as a Multifunctional Regulator of Gut Health: Integrative Mechanisms Involving Inflammation, Barrier Integrity, and Gut-Organ Axis.
    Weiyu Zhu, Chaoyi Jia, Tianyuan Fei, Zhaoyue Chen, Zhanyu Lin, Yu Pan, Guobing Ma, Fengjun Ma.
      Intestinal health is sustained by coordinated control of mucosal immunity, epithelial barrier integrity, and the gut microbiota and its metabolites. Disruption of these tightly coupled systems contributes to a wide spectrum of disorders, ranging from infectious enteritis and inflammatory bowel disease (IBD) to ischemia-reperfusion injury and metabolic dysfunction with extra-intestinal sequelae. Baicalin (BAI), a major flavonoid from Scutellaria baicalensis, has emerged as a multi-level regulator of gut homeostasis. Across diverse preclinical models, BAI attenuates inflammatory signaling and frequently converges on NF-κB-centered networks; it also rebalances immune responses by modulating macrophage polarization and T-cell subsets, limits oxidative and ferroptotic damage through cytoprotective programs, and restores barrier function by preserving tight junctions and mucus-layer defenses. In parallel, BAI remodels microbial community structure and microbial metabolites, including short-chain fatty acids and bile-acid signaling, providing a plausible basis for benefits along gut-organ axes such as the gut-liver and gut-metabolic axes. This review integrates mechanistic evidence across these three pillars and highlights key translational gaps, including limited oral bioavailability, incomplete causal validation of proposed targets, and the need to disentangle BAI from active metabolites. We further discuss derivative design, formulation, and combination strategies to improve exposure and accelerate clinical translation.
    Keywords:  baicalin; barrier integrity; gut health; gut-organ axis; inflammation
    DOI:  https://doi.org/10.2147/DDDT.S585486
  48. Front Aging Neurosci. 2026 ;18 1771904
    Diet, gut microbiome, and cognition in neurodegeneration: a review and methodological framework.
    Jacob Raber, Thomas J Sharpton.
      The gut microbiome influences brain function through the gut-brain axis via synthesis of neurotransmitters, production of metabolites affecting epithelial barrier integrity and immune modulation and signaling through the vagus nerve. In humans, microbiome diversity reflects healthy aging and predicts survival, while dysbiosis is increasingly implicated in neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ALS. Fecal transplant studies in germ-free mice demonstrate that microbiome alterations are sufficient to induce cognitive and neuropathological phenotypes, supporting causality in preclinical models. Genetic risk factors and environmental exposures affect both neurodegeneration risk and microbiome composition. In this review, we synthesize evidence from human cohorts and preclinical models on the gut-brain axis in cognitive health and disease. We then present a methodological framework for diet-microbiome-cognition research, addressing causal inference through mediation analysis, supervised approaches for deriving diet scores, validation strategies, and individual heterogeneity. This framework can guide development of microbiome-targeted dietary interventions to improve cognitive outcomes.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; cognition; diet questionnaire; gut microbiome
    DOI:  https://doi.org/10.3389/fnagi.2026.1771904
  49. Eur J Med Chem. 2026 Mar 04. pii: S0223-5234(26)00172-8. [Epub ahead of print]309 118727
    The role of zinc transporter 1 (ZnT1) in health and disease: From molecular mechanisms to therapeutic opportunities.
    ZiTong Yang, QiYao Xu, XiaoTing Yang, Tian Zhou, Yan Xiong, Ying Liu, Dunkai Li, Hui Wu.
      Zinc transporter 1 (ZnT1/SLC30A1) is a major plasma membrane-localized zinc efflux transporter and acts as a central regulator of cellular metal homeostasis. Beyond exporting Zn2+, recent evidence reveals that ZnT1 also transports Cu2+ and serves as a molecular hub linking zinc-copper interplay, redox balance, immune signaling and programmed cell death. This review summarizes current advances in ZnT1 structure, transport mechanism, regulatory networks and physiological roles across the gut-liver-immune-neuro-cardiovascular axis. We further outline its pathological involvement in Wilson disease, amyotrophic lateral sclerosis, cancer and inflammatory disorders, highlighting ferroptosis, cuproptosis and metabolic reprogramming as key downstream consequences of ZnT1 dysregulation. Emerging therapeutic approaches include small-molecule modulators, RNA-based regulation, antibody targeting and metal-based interventions. Although challenges remain-such as tissue specificity, systemic toxicity and biomarker development-ZnT1 is rapidly evolving from a basic transport protein to a promising precision medicine target. Continued efforts in structural biology, single-cell metallomics and targeted delivery systems will accelerate its clinical translation.
    Keywords:  Cuproptosis; Ferroptosis; Metal transporter; Therapeutic target; Zinc homeostasis; ZnT1
    DOI:  https://doi.org/10.1016/j.ejmech.2026.118727
  50. J Inflamm Res. 2026 ;19 542308
    Rewiring the Lung-CNS Axis After Spinal Cord Injury.
    HaiRong Wu, Xiaolong Li, Wenjun Zhao, Yihan Li, Hang Zhang, Heng Yin, Xiaofeng Gu.
      Spinal cord injury (SCI) is a catastrophic disorder of the central nervous system, most commonly resulting from traumatic events such as motor vehicle collisions or falls, but it can also arise from non-traumatic causes including neoplastic, infectious, or degenerative diseases. Respiratory complications are among the most frequent and life-threatening sequelae of SCI. In the acute phase, up to 80% of patients experience respiratory dysfunction, including pneumonia, atelectasis, and respiratory failure. These issues are particularly pronounced in individuals with high cervical injuries, where diaphragmatic and intercostal muscle paralysis impairs effective ventilation and clearance of secretions, substantially increasing the risk of infection. Emerging evidence underscores the bidirectional interplay between pulmonary pathology and central nervous system injury. SCI-induced autonomic dysfunction alters immune regulation, heightening susceptibility to pulmonary infections. Conversely, pulmonary complications can amplify systemic inflammatory responses, which may exacerbate neurological deterioration. Understanding the complex interactions between respiratory complications and SCI pathophysiology is essential for improving patient outcomes. This review therefore focuses on elucidating the mechanisms of pulmonary complications post-SCI and exploring therapeutic strategies to mitigate their impact on neurological recovery.
    Keywords:  lung–CNS axis; neuroimmune interaction; pulmonary microenvironment; spinal cord injury
    DOI:  https://doi.org/10.2147/JIR.S542308
  51. Curr Neuropharmacol. 2026 Mar 13.
    Decoding the Blood-Brain Barrier: Innovative and Scalable Open-Source Machine Learning Model for Drug Permeability.
    Anastasiia M Isakova, Dmitrii O Shkil, Ilya S Steshin, Ekaterina V Skorb, Maxim V Fedorov, Sergey Shityakov.
       INTRODUCTION: The permeability of the blood-brain barrier (BBB) is an important property for potential drugs. Various in vitro and in vivo methods have been established to measure bloodbrain transport. Nevertheless, empirical assessment of the blood-brain barrier (BBB) for all drug candidates is both resource-intensive and costly.
    METHODS: In this study, we present practical and reliable machine learning methods developed using extensive datasets to assess BBB permeability.
    RESULTS: The best model for the BBB classification task reached the ROC-AUCcv value of 0.963, whereas our best BBB regression model achieved R2 = 0.954, Q2 = 0.728, and RMSEcv = 0.321.
    DISCUSSION: The study introduced the novel approach of using classification labels as additional descriptors for regression tasks, which significantly improved model performance. The models demonstrated strong generalization capabilities, with validation metrics closely matching crossvalidation results.
    CONCLUSION: Due to the significantly expanded dimensions of the training dataset collected from a variety of sources, the regression model we developed exhibits greater robustness compared to previously published models. We also demonstrated for the first time the idea of using a classification label as an additional descriptor for a regression task. Among the most important things is the fact that all our models are publicly available and can be used by scientists for their own research.
    Keywords:  Blood-brain barrier permeability; classification; deep learning; machine learning; regression.
    DOI:  https://doi.org/10.2174/011570159X396302251128110053
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