bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–05–10
38 papers selected by
Luca Bolliger, lxBio
  1. miRNAs in Amyotrophic Lateral Sclerosis: Tiny Molecules, Tremendous Impact.
  2. Conjecture for a free radical epimerization process in Alzheimer, Parkinson, Lewy body, amyotrophic lateral sclerosis, progressive Supranuclear Palsy and Creutzfeldt Jakob diseases.
  3. Gene Targeted Therapies for Neurodegenerative Disorders: Strategies and Implications in ALS and SMA.
  4. Biomaterials and Nanoparticle-Based Therapeutics in Neurodegenerative Diseases: Bridging the Gap Between Innovation and Translation.
  5. Novel Cellular Signalling Axes in Neurodegenerative Diseases: From NLRP3 Inflammasome to Wnt/β-Catenin and Hippo-YAP Pathways.
  6. Targeting the NAD+-PARP1-XRCC1 axis in ALS.
  7. Elevated plasma sTREM2 reflects microglial activation but lacks diagnostic and clinical relevance in amyotrophic lateral sclerosis.
  8. Mechanistic insights and therapeutic potential of targeting the cGAS-STING pathway in neurodegenerative diseases.
  9. Cyclodextrin-Based Strategies for Brain Drug Delivery: Mechanistic Insights into Blood-Brain Barrier Transport and Therapeutic Applications.
  10. Pre-Diagnostic Plasma Carotenoids, Tocopherols and Retinol Levels, and Risk of Amyotrophic Lateral Sclerosis.
  11. Predictive Cellular Signatures from Live Human Motor Neurons Distinguish TDP-43 ALS and Enable ALS Subtype Stratification.
  12. "Silent Echoes of the Day: Dream Content Analysis in Amyotrophic Lateral Sclerosis".
  13. Mapping the Polar Neuro-Interactome of Garcinia mangostana Against the AD-PD-ALS Nexus.
  14. Multimodal strategies for diagnosis, stratification, and therapeutic monitoring in ALS.
  15. Head trauma and environment progression of amyotrophic lateral sclerosis: long-term data from the National ALS Registry.
  16. [A personal exploration of oral health in amyotrophic lateral sclerosis].
  17. Lipid Dysregulation as a Central Contributor of Neurodegenerative Diseases: Emerging Therapeutic Targets and Strategies.
  18. Targeting the integrated stress response or Ataxin-2 alleviates neurodegeneration in PolyGR models of C9orf72 associated frontotemporal dementia and amyotrophic lateral sclerosis.
  19. Relationship between grip strength, functional outcome, and health-related quality of life measurements in amyotrophic lateral sclerosis patients.
  20. Phosphorylated Tau at Threonine 181 Is Elevated in Amyotrophic Lateral Sclerosis Plasma.
  21. Exosomes as Advanced Nanocarriers: Overcoming the Blood-Brain Barrier for Targeted Therapeutic Delivery in Neurodegenerative Diseases.
  22. Pridopidine Protects ALS Patient-Derived Neural Progenitor Cells via Sigma-1 Receptor Activation.
  23. Intranasal vs. Device-Assisted Drug Delivery: Advantages and Limitations for the Delivery of Biopharmaceuticals to the CNS.
  24. King's stages of amyotrophic lateral sclerosis: an 18F-FDG-PET study of brain connectivity.
  25. Cellular Senescence in Neurodegeneration: From Cell Types to Therapeutic Opportunities.
  26. Molecular Modulation of the Crosstalk Between TDP-43 and SOD1.
  27. TMEM106B C-terminal fragments drive nucleocytoplasmic transport failure and TDP-43 mislocalization in the aging human brain.
  28. Impact of Oxidative Stress-Driven Ferroptosis in Neurodegeneration.
  29. Neuromuscular junction innervation and motor function are preserved by restoring muscarinic signaling in perisynaptic glia in ALS.
  30. Advances in neuropharmacology: Innovative drug strategies targeting synaptic plasticity, neuroinflammation, and ion channel regulation for future CNS treatments.
  31. Plasma Autoantibodies Against Neurodegeneration-Related Antigens in Dementia and Elevated Chi3Li Autoantibodies in Mild Cognitive Impairment.
  32. Resveratrol and the neuroinflammation axis in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and cerebral ischemia.
  33. Proteasomal-dependent CHK1 degradation leads to DNA damage accumulation in ALS cellular model systems.
  34. Catching a ride: Nanoparticles bypass the blood-brain barrier.
  35. Nanomedicine for Alzheimer's Disease: Diagnostic and Therapeutic Progress.
  36. Impact of Plasma p-tau181 on Cognition, Motor Phenotypes, and Disease Course in ALS.
  37. Microbial tryptophan metabolites modulate blood-brain and gut barriers in vitro.
  38. Estimation of Various Physiological Parameters Affecting Amyloid Plaque Distribution of a Novel MRI Contrast Agent in the Brain of Alzheimer's Disease Transgenic Mice.
  1. Mol Neurobiol. 2026 May 03. pii: 605. [Epub ahead of print]63(1):
    miRNAs in Amyotrophic Lateral Sclerosis: Tiny Molecules, Tremendous Impact.
    Sherif S Abdel Mageed, Ghadir A Sayed, Ahmed Mahdy, Walaa A El-Dakroury, Ahmed O Abdulkader, Hebatallah Ahmed Mohamed Moustafa, Reda M Mansour, Osama A Mohammed, Mohammed S Elballal, Ahmed E Elesawy, Ahmed S Doghish.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder distinguished by progressive motor neuron degeneration, with diverse clinical manifestations and complex genetic and environmental triggers. The variability in disease progression underscores the necessity for tailored diagnostic and therapeutic approaches. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, have emerged as promising biomarkers and therapeutic targets in ALS. Dysregulation of specific miRNAs has been linked to mechanisms of ALS, including neuromuscular dysfunction, neuroinflammation, and neuronal survival/apoptosis. The potential of miRNA-based therapies, such as mimics and inhibitors, offers a more integrated approach by modulating entire disease networks, rather than targeting isolated pathways. However, challenges persist, particularly in delivering these therapies efficiently across the blood-brain barrier and minimizing off-target effects. Current delivery strategies involving nanoparticles, viral vectors, and exosome-based approaches require optimization for clinical use. This review synthesizes the latest research on miRNA-mediated mechanisms in ALS, evaluating their diagnostic, prognostic, and therapeutic potential, while highlighting the current limitations in clinical validation. It underscores the importance of standardized methodologies, multi-omics integration, and rigorous validation to facilitate the clinical translation of miRNA-based strategies. Standardized protocols and multicenter validation in large cohorts are essential to confirm the diagnostic accuracy of miRNAs, paving the way for their clinical application in ALS precision medicine.
    Keywords:  Amyotrophic Lateral Sclerosis (ALS); Biomarkers; MiRNAs; Neurodegeneration; Precision Medicine; Therapeutic Targets
    DOI:  https://doi.org/10.1007/s12035-026-05880-2
  2. Exp Neurol. 2026 May 05. pii: S0014-4886(26)00176-7. [Epub ahead of print] 115812
    Conjecture for a free radical epimerization process in Alzheimer, Parkinson, Lewy body, amyotrophic lateral sclerosis, progressive Supranuclear Palsy and Creutzfeldt Jakob diseases.
    Roger Deloncle.
      Brain protease-resistant misfolded proteins have been described in Alzheimer (AD), Parkinson (PD), Lewy Body (LBD), Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy (PSP) and Creutzfeldt Jakob (CJD) diseases. The role of free radicals in generating these protease resistant structures has been experimentally demonstrated in prion bovine spongiform encephalopathy (BSE), when manganese is substituted for copper (Cu), in bovine brain homogenates in reductive medium, while Cu protective effect against free radicals can be restored by Cu supplementation in oxidative medium. These facts can suggest a free radical-induced epimerization process in neuroprotein misfolding leading to the transformation of physiological L-amino acid brain proteins into abnormal D-structures which will be deposited in the brain as observed in neurodegenerative diseased brains. A blood Cu increase, not ceruloplasmin (CP) bound correlated with a Cu increase in the cerebrospinal fluid (CSF) and a Cu decrease in the brain have been described in AD, PD, ALS, or CJD. This indicates that following neuronal death, Cu might be expelled from brain proteins and subsequent to redistribution between brain, CSF and blood, it will result a brain Cu deficiency and a decrease in Cu brain protection against free radicals. In the aim of repairing this deficiency and slow down the neurodegenerative disease process, a brain Cu complexes vectorization through the blood-brain barrier might restore brain Cu homeostasis.
    Keywords:  Blood copper increase; Brain copper decrease; D amino acids; Free radical epimerization; Neurodegenerative diseases; Neuronal death; Protein misfolding
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115812
  3. Genes (Basel). 2026 Apr 01. pii: 419. [Epub ahead of print]17(4):
    Gene Targeted Therapies for Neurodegenerative Disorders: Strategies and Implications in ALS and SMA.
    Ayse Yesbek Kaymaz, Gamze Bora-Akoğlu, Hayat Erdem Yurter, Christopher Grunseich.
      Advances in technology have provided a better understanding of the genetic basis of neurodegenerative disorders and their underlying molecular pathophysiology. However, treating these disorders with conventional strategies is a major challenge. The approval of gene targeted therapy for spinal muscular atrophy (SMA) has laid the foundation for developing highly personalized therapies for other neurodegenerative disorders. As intensive research and efforts to advance gene targeted therapies continue, this review provides an overview of viral and non-viral vectors and delivery methods, as well as treatment strategies, including gene addition, replacement, editing, silencing, and splice modulation. Gene targeted approaches and clinical trials for SMA and amyotrophic lateral sclerosis (ALS) have demonstrated success, and additional studies are in progress. The design of efficient clinical trials which facilitate successful translation into clinical practice is of critical importance. Key considerations include the selection of appropriate disease models, understanding the natural history of the disease, and establishing well-defined outcome measures to assess prognosis of the disease and therapeutic efficacy. Finally, the precision of CRISPR-based gene editing offers the potential for one-time corrective therapies for monogenic disorders like SMA and SOD1-ALS.
    Keywords:  amyotrophic lateral sclerosis; clinical trial readiness; gene therapy; spinal muscular atrophy
    DOI:  https://doi.org/10.3390/genes17040419
  4. ACS Chem Neurosci. 2026 May 08.
    Biomaterials and Nanoparticle-Based Therapeutics in Neurodegenerative Diseases: Bridging the Gap Between Innovation and Translation.
    Dia Panchal, Dattavi Solanki, Raghu Solanki, Amit K Yadav, Dhiraj Bhatia, Pankaj Yadav.
      Neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and multiple sclerosis, represent a growing global health crisis characterized by irreversible neuronal loss, protein aggregation, chronic neuroinflammation, and mitochondrial dysfunction. Central to their therapeutic intractability is the blood-brain barrier (BBB), a highly selective neurovascular interface that excludes nearly 98% of conventional pharmacological agents from the central nervous system (CNS). Nanoparticle- and biomaterial-based delivery platforms have emerged as promising strategies to overcome these barriers, encompassing liposomes, polymeric nanoparticles, engineered exosomes, inorganic nanoparticles, and hydrogel scaffolds capable of enabling targeted CNS drug delivery. This Review systematically evaluates the landscape of nanomaterial-based neurotherapeutics across disease-specific pathological contexts, critically analyzing translational failure mechanisms including limited parenchymal brain exposure, receptor saturation during transcytosis, protein corona-mediated immune clearance, and nanoscale toxicity in postmitotic neural tissue. Preclinical-to-clinical translational gaps arising from interspecies BBB transporter heterogeneity and pharmacokinetic divergence are examined alongside manufacturing and regulatory barriers impeding Good Manufacturing Practice (GMP)-scale production. Emerging convergence strategies─including AI-integrated design, hybrid physiologically based pharmacokinetic modeling, theranostic nanoplatforms, and wearable bioresponsive delivery systems─are evaluated for their capacity to address these limitations. The review concludes by proposing a framework for developing clinically viable, disease-modifying CNS nanomedicines.
    Keywords:  CNS nanomedicine; blood−brain barrier; liposomes; nanoparticle drug delivery; neurodegeneration; theranostics; translational pharmacology
    DOI:  https://doi.org/10.1021/acschemneuro.6c00245
  5. J Biochem Mol Toxicol. 2026 May;40(5): e70880
    Novel Cellular Signalling Axes in Neurodegenerative Diseases: From NLRP3 Inflammasome to Wnt/β-Catenin and Hippo-YAP Pathways.
    Kuldeep Singh, Iftakhar Ahmad, Divya Jain, Tasmia Jahin Mim, Abdullah Al Noman, Md Piar Rahaman Shihab, Suresh Babu Kondaveeti, Jeetendra Kumar Gupta, Pranay Wal.
      Neurodegenerative diseases (NDs), including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), are characterised by impaired cellular homeostasis and progressive neuronal loss. Emerging evidence highlights the critical role of cellular signalling pathways in the progression and pathogenesis of these disorders. With a focus on the NLRP3 inflammasome, Wnt/β-catenin, and Hippo-YAP cascades, this review focuses on new signalling pathways linked to neurodegenerative disorders. Among them, the NLRP3 inflammasome is a crucial mediator of neuroinflammation, causing neuronal damage and persistent immune activation. In contrast, these pathways regulate neurogenesis, synaptic plasticity, and cell survival, offering potential neuroprotective functions. Dysregulation of these pathways disrupts cellular integrity, exacerbates disease progression, and represents a convergence point for therapeutic intervention. In NDs, knowing how these pathways interact offers fresh perspectives on disease processes and finds new targets for the creation of disease-modifying treatments.
    Keywords:  Alzheimer's disease; Hippo‐YAP pathway; NLRP3 inflammasome; Parkinson's disease; Wnt/β‐catenin signalling; cellular signalling; neurodegenerative diseases; neuroinflammation; neuronal survival; synaptic plasticity
    DOI:  https://doi.org/10.1002/jbt.70880
  6. Trends Mol Med. 2026 May 04. pii: S1471-4914(26)00086-9. [Epub ahead of print]
    Targeting the NAD+-PARP1-XRCC1 axis in ALS.
    Md Ibrahim, Md Shahadat Hossain, Lezanne Ooi, Md Mahmudul Hasan, Shandra Ahsan, Aliasger K Salem, Gary A Piazza, Xiaodong Feng, Fakhrul Ahsan.
      Amyotrophic lateral sclerosis (ALS) remains a fatal neurodegenerative disease with few effective therapies. Emerging evidence indicates that oxidative DNA damage, defective base excision and single-strand break repair, and progressive NAD+ depletion contribute to motor neuron degeneration. The NAD+-PARP1-XRCC1 axis sits at the intersection of genome maintenance and metabolic control, linking DNA damage signaling to cellular bioenergetics. When dysregulated, this pathway may drive persistent PARP1 activation, failed repair, and energetic collapse. In this review, we integrate mechanistic and translational evidence supporting this axis as a therapeutic target in ALS. We propose a staged translational framework that prioritizes repurposable low-trapping PARP1 inhibitors combined with NAD+ support, followed by central nervous system-directed RNA-lipid nanoparticle delivery of repair factors, with poly(ADP-ribose) and NAD+ metabolites as pharmacodynamic biomarkers.
    Keywords:  DNA damage repair; NAD(+) metabolism; PARP1 hyperactivation; XRCC1 dysfunction; amyotrophic lateral sclerosis; neuroprotection
    DOI:  https://doi.org/10.1016/j.molmed.2026.04.004
  7. Neurobiol Dis. 2026 Apr 30. pii: S0969-9961(26)00175-0. [Epub ahead of print]224 107430
    Elevated plasma sTREM2 reflects microglial activation but lacks diagnostic and clinical relevance in amyotrophic lateral sclerosis.
    Gianmaria Senerchia, Valentina Virginia Iuzzolino, Myriam Spisto, Fabiana Panico, Carmela Polito, Lucia Aruta, Mariano Fiorenza, Rosa Sirica, Daniela Terracciano, Raffaele Dubbioso.
      Microglial activation contributes to the neuroinflammatory response in amyotrophic lateral sclerosis (ALS). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) reflects microglial activity in several neurodegenerative disorders, but its role in ALS remains unclear. We evaluated plasma sTREM2 as a marker of microglial activation in ALS and compared its diagnostic performance with established blood biomarkers of neurodegeneration. Plasma sTREM2, neurofilament light chain (NfL), phosphorylated tau181 (Ptau181), and glial fibrillary acidic protein (GFAP) were measured in 100 patients with ALS, 30 healthy controls, and 30 disease mimics. Group differences were assessed using general linear models adjusted for age and sex. Associations with clinical variables and inflammatory markers were tested using Spearman correlation, and diagnostic performance was evaluated using receiver operating characteristic curves. Plasma sTREM2 differed across groups (p = 0.016), with higher levels in ALS compared with healthy controls (p = 0.013) and in mimics compared with healthy controls (p = 0.007), but no difference between ALS and mimics (p = 0.394). Discrimination between ALS and healthy controls was modest (area under the curve 0.677), with no discrimination between ALS and mimics (area under the curve 0.512). No association was found between sTREM2 and disease severity or inflammatory markers (all p > 0.10). Plasma sTREM2 increases in ALS but lacks diagnostic specificity and clinical associations, supporting its role as a nonspecific marker of neuroimmune activation rather than a biomarker of disease-related neurodegeneration.
    Keywords:  ALS; Fluid biomarker; Microglia; Neuroinflammation; sTREM2
    DOI:  https://doi.org/10.1016/j.nbd.2026.107430
  8. J Neuroinflammation. 2026 May 07.
    Mechanistic insights and therapeutic potential of targeting the cGAS-STING pathway in neurodegenerative diseases.
    Huilin Liu, Chun Hu, Hongdou Liu, Ziqing Gong, Shilong Jiang, Junkai Xie, Yongtao Li, Chong Liu, Ying Wang, Chan Zou, Guoping Yang.
      The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central cytosolic DNA-sensing module that links DNA damage and mitochondrial dysfunction to innate immune activation. Here, we focus on canonical cGAS-STING signaling in the central nervous system (CNS) and discuss non-canonical branches only when directly relevant to neurodegeneration. We summarize structural and activation-termination mechanisms and synthesize cell-type-biased outputs across microglia, astrocytes, neurons, and oligodendroglial lineage cells. We then integrate Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease by mapping shared DNA-stress triggers to multicellular amplification loops and by grading causal evidence from genetic perturbation, pharmacological pathway interference, and correlative human datasets. Finally, we classify inhibitor modalities and emerging enabling technologies while emphasizing translational constraints, including blood-brain barrier (BBB) delivery, long-term safety, human STING-allele diversity, and pharmacodynamic biomarkers. Collectively, we propose an evidence-calibrated framework for judging when cGAS-STING is most plausibly positioned as a causal node, a permissive amplifier, or a secondary correlate in neurodegenerative disease, and where therapeutic translation should proceed cautiously.
    Keywords:  Cellular effector responses; Drug discovery; Innate immunity; Neurodegenerative diseases; cGAS-STING
    DOI:  https://doi.org/10.1186/s12974-026-03815-1
  9. Pharmaceutics. 2026 Apr 07. pii: 451. [Epub ahead of print]18(4):
    Cyclodextrin-Based Strategies for Brain Drug Delivery: Mechanistic Insights into Blood-Brain Barrier Transport and Therapeutic Applications.
    Pirscoveanu Denisa Floriana Vasilica, Pluta Ion Dorin, Carmen Vladulescu, Cristina Popescu, Diana-Maria Trasca, Kristina Radivojevic, Renata Maria Varut, Ștefănița Bianca Vintilescu, Mioara Desdemona Stepan, George Alin Stoica.
      Cyclodextrins (CDs) have gained increasing attention as versatile platforms for enhancing drug delivery to the central nervous system, particularly in overcoming the restrictive properties of the blood-brain barrier (BBB). Owing to their unique cyclic oligosaccharide structure, CDs are capable of forming inclusion complexes with a wide range of therapeutic agents, thereby improving their solubility, stability, and bioavailability. In addition to their role as excipients, growing evidence indicates that CDs can actively modulate biological processes, including membrane fluidity and cholesterol homeostasis, which are critical factors in neurological disorders. This review explores the application of CDs in facilitating drug transport across the BBB through multiple mechanisms, including carrier-mediated transport, receptor-mediated transcytosis, and nanoparticle-based delivery systems. Special emphasis is placed on their use in the treatment of neurodegenerative and neurological diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Niemann-Pick type C disease, and other central nervous system disorders. In these contexts, CD-based formulations have demonstrated the ability to enhance brain targeting, reduce pathological protein aggregation, and improve therapeutic outcomes in preclinical models. This review uniquely integrates cyclodextrin's physicochemical properties with specific blood-brain barrier transport mechanisms, proposing a structure-transport-therapy framework that enables a more predictive understanding of brain-targeted drug delivery.
    Keywords:  blood–brain barrier; brain-targeted drug delivery; cyclodextrins; nanoparticles; neurodegenerative diseases; receptor-mediated transcytosis
    DOI:  https://doi.org/10.3390/pharmaceutics18040451
  10. Ann Neurol. 2026 May 04.
    Pre-Diagnostic Plasma Carotenoids, Tocopherols and Retinol Levels, and Risk of Amyotrophic Lateral Sclerosis.
    Éilis J O'Reilly, Kjetil Bjornevik, Jeremy D Furtado, Alpa V Patel, Ying Wang, Laurence N Kolonel, Loïc Le Marchand, Alberto Ascherio.
       OBJECTIVE: Our goal was to examine whether pre-diagnostic plasma carotenoids and tocopherols are associated with amyotrophic lateral sclerosis (ALS).
    METHODS: A nested case-control study within 4 United States cohorts, where 154 participants with pre-diagnostic blood-draw, were diagnosed during follow-up with amyotrophic lateral sclerosis (ALS). Controls were randomly selected from participants alive on the date a case was diagnosed, matched 2:1 by cohort, sex, age, race/ethnicity, fasting-status, time of blood-draw. Carotenoid and tocopherol levels were quantified by high-performance liquid-chromatography with diode array-detector. ALS incidence or death rate ratios (RR) were estimated using conditional logistic regression adjusting for body mass index, smoking status, physical activity, cholesterol, and urate levels.
    RESULTS: The association between beta-carotene and ALS varied by sex (p-for-interaction = 0.007). After matched- and multivariable-adjustment, women with higher cis-, trans- and total beta-carotene had lower incidence of ALS (RR for 1-standard deviation [SD] increase in total beta-carotene: 0.68; 95% CI: 0.48-0.98; p = 0.038), whereas a positive association was seen in men (1-SD increase: RR = 1.44; 95% CI: 1.03-2.01; p = 0.033). However, after further adjustment for other correlated carotenoids, the association in men was attenuated, whereas it remained significant in women. Women with higher beta-cryptoxanthin, but not men, had a lower risk of ALS (1-SD increase: RR = 0.67; 95% CI: 0.48-0.94; p = 0.02; p-for-interaction = 0.12). Alpha-carotene, lutein-zeaxanthin, lycopene, retinol, and tocopherols were not associated with ALS, except for a borderline inverse association of gamma-tocopherol in men (RR = 0.74; 95% CI: 0.54-1.01; p = 0.059).
    INTERPRETATION: Higher pre-diagnostic plasma levels of beta-carotene and beta-cryptoxanthin in women and gamma-tocopherol in men were suggestively associated with lower ALS risk. Other carotenoids or tocopherols were not clearly associated with ALS. ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78240
  11. bioRxiv. 2026 Apr 24. pii: 2026.04.22.719920. [Epub ahead of print]
    Predictive Cellular Signatures from Live Human Motor Neurons Distinguish TDP-43 ALS and Enable ALS Subtype Stratification.
    Julia Kaye, Naufa Amirani, Úna Chan, Noura Al Bistami, Zohreh Faghihmonzavi, Monika Ahirwar, Reuben Thomas, Wesley Robinson, Edward Vertudes, Krishna Raja, Mariya Barch, Drew Linsley, Ana Jovicic, Steven Finkbeiner.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive, rapid deterioration of motor neurons (MNs). Rare mutations in a handful of genes are sufficient to cause ALS; however, 90% of ALS cases are not linked to these genes and their underlying cause remains unknown. Abnormal subcellular distribution, structure or aggregation of the TDP-43 protein are nearly universal hallmarks of the disease, suggesting a shared molecular mechanism across both genetic and sporadic ALS (sALS). However, the heterogeneity of the ALS clinical syndrome suggests that the underlying mechanisms culminating in ALS and TDP-43 pathology may partly differ among individuals and may need to be understood to develop successful therapies that target subgroups of patients. Here, we harnessed the power of machine learning (ML) to begin to decode, in a systematic and unbiased fashion, the cellular signatures of ALS. We used high-content imaging of live, human iPSC-derived motor neurons (iMNs) from ALS patients or gene-edited and gene-corrected TDP-43 mutant lines to train shallow connected ML algorithms (SMLs) and deep convolutional neural networks (DNNs). Our models identified and distinguished mutant and control iMNs with moderately high accuracy. We then used explainability methods to uncover the discriminating cellular signals and found that the strongest ones mapped to the nuclear area, suggesting underlying alterations within the nucleus. We validated this finding by revealing that TDP-43 mutant iMNs display alterations in nucleocytoplasmic shuttling and cellular integrity. Further, a time-interaction ML model uncovered dynamic morphological transitions preceding degeneration, offering a window into early pathogenic events as well as neurodevelopmental changes. Extending our ML pipeline to iMNs with mutations in the ALS gene C9orf72 or derived from sALS revealed both overlapping and distinguishable signatures, suggesting shared yet distinct mechanistic pathways. Together, these findings establish ML-driven phenotypic profiling as a powerful approach to stratify people with ALS, help disentangle the molecular heterogeneity of ALS and produce a more holistic phenotypic definition in cell-based models, and ultimately find causes and treatments. This strategy offers a scalable and innovative paradigm for uncovering early disease mechanisms not only in ALS but potentially across a spectrum of neurodegenerative and sporadic disorders.
    DOI:  https://doi.org/10.64898/2026.04.22.719920
  12. Brain Behav. 2026 May;16(5): e71387
    "Silent Echoes of the Day: Dream Content Analysis in Amyotrophic Lateral Sclerosis".
    Alessandro Bombaci, Alessandra Giordano, Ilaria Lavalle, Alice Magnino, Andrea Calvo, Adriano Chiò, Alessandro Cicolin.
       BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of upper and lower motor neurons, leading to muscle atrophy, weakness, and respiratory failure. Numerous studies evaluated the impact of diseases on dream content, and the dream content analysis may be considered an interesting tool in the study of the internalization of the consequences of significant life changes. The study of ALS patients' dream content has been mostly neglected in the literature. This study investigated the dream content in a population affected by ALS.
    MATERIAL AND METHODS: We evaluated all consecutive outpatients referred to our ALS Centre using a weekly diary of dreams. Dream contents were coded according to the Hall and Van de Castle coding system.
    RESULTS: Sixty-eight patients completed the study. We collected 127 dreams (females 39.4%) (males 60.6%). Males showed a reduced presence of friends, anatomical elements, aggression, friendship, and sexuality. Instead, we found an increased presence of family members, situations in which the dreamer initiates aggressive action and familiar settings. In the female sample, we found a decreased presence of friends, aggressive and friendly elements, sex-related content, and misfortune, while an increase in animal content.
    CONCLUSIONS: Our results demonstrate that dream content in ALS patients differs from that of healthy subjects, and we noticed some gender differences among ALS patients. The dream content can offer insights into ALS patients' mental state and may improve clinicians' ability to support their patients during their therapeutic course.
    Keywords:  ALS; dream; neurodegeneration; sleep
    DOI:  https://doi.org/10.1002/brb3.71387
  13. Life (Basel). 2026 Apr 01. pii: 580. [Epub ahead of print]16(4):
    Mapping the Polar Neuro-Interactome of Garcinia mangostana Against the AD-PD-ALS Nexus.
    Rahni Hossain, Sirirat Surinkaew, Pradoldej Sompol, Nasmah K Bastaki, Rifat Jafrin, Nazim Sekeroglu, Jitbanjong Tangpong.
      Background/Objectives: Neurodegenerative diseases like Alzheimer's, Parkinson's, and Amyotrophic lateral sclerosis (ALS) share common molecular pathways, including neuroinflammation and oxidative stress, which complicate the effectiveness of single-target treatments. Garcinia mangostana L. (mangosteen) has shown neuroprotective properties, but previous studies focused on lipophilic xanthones, which have poor bioavailability and uncertain blood-brain barrier permeability. Methods: In the current study, polar metabolites from G. mangostana peel aqueous extract (GMPE) were assessed for potential multi-target interactions via UHPLC-QTOF-MS-based metabolomics, systems pharmacology, and molecular docking analysis. Further, in silico ADMET screening and network-based analyses assessed for overlap between GMPE compounds and genes associated with neurodegeneration (AD, PD, ALS). Results: Analysis of genes linked to AD, PD, and ALS revealed 121 common molecular targets influenced by GMPE metabolites. Network and enrichment analyses indicated that the compounds derived from GMPE may be involved in common pathways related to oxidative stress, neuroinflammation, and neuronal survival. Molecular docking analyses suggest that selected metabolites are likely to exhibit moderate binding affinities to their respective protein targets. Conclusions: The results presented in this study provide evidence that GMPE may possess potential multi-target interactions within common neurodegenerative pathways. However, since the data are based on computational and predictive approaches, these results should be considered hypothesis-generating and warrant further experimental validation.
    Keywords:  Alzheimer’s disease; Garcinia mangostana; Parkinson’s disease; UHPLC–QTOF–MS metabolomics; amyotrophic lateral sclerosis; blood–brain barrier permeability; neurodegenerative diseases; systems pharmacology
    DOI:  https://doi.org/10.3390/life16040580
  14. Neurosci Biobehav Rev. 2026 May 06. pii: S0149-7634(26)00184-3. [Epub ahead of print] 106727
    Multimodal strategies for diagnosis, stratification, and therapeutic monitoring in ALS.
    Rafael López-Blanch, María Oriol-Caballo, José M Estrela, Elena Obrador.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder of motor neurons (MN) that is currently diagnosed through a prolonged process of exclusion, often delaying intervention. This review provides an overview of fluid, imaging, electrophysiological, and genetic biomarkers, explicitly linking each modality to early detection, patient stratification, disease monitoring, therapeutic development, and clinical trial design. Fluid biomarkers (i.e., neurofilament light chain, phosphorylated neurofilament heavy chain, inflammatory cytokines, microRNAs, and proteins in blood or cerebrospinal fluid) reflect neuronal injury and/or disease activity, enabling early identification of pres-ymptomatic individuals and longitudinal tracking of neurodegeneration. Imaging biomarkers, such as structural and diffusion MRI of the motor cortex, corticospinal tracts, and spinal cord, as well as PET imaging neuroinflammation or metabolism, provide objective measures of MN degeneration and extra-motor involvement. Electrophysiological biomarkers, including high-density electromyography, motor unit number, transcranial magnetic stimulation, and electrical impedance myography, quantitatively assess upper and lower MN loss and functional reserve. Genetic biomarkers, encompassing variants in genes such as C9orf72, SOD1, FUS, and TARDBP, enable presymptomatic screening and molecular stratification. In this context, transposable elements have emerged as an additional layer linking genomic variation and RNA dysregulation. We highlight the importance of multimodal and stage-specific biomarker integration to improve diagnostic accuracy and illuminate distinct disease phases. This approach supports stratification by progression rate or molecular subtype, enrichment of clinical trial cohorts, and the development of surrogate endpoints. We conclude by discussing current challenges, including disease heterogeneity and assay standardization, and outline future directions toward biomarker-driven precision medicine in ALS.
    Keywords:  Amyotrophic lateral sclerosis; biomarkers; motor neuron; neurodegeneration; precision medicine
    DOI:  https://doi.org/10.1016/j.neubiorev.2026.106727
  15. BMJ Neurol Open. 2026 ;8(1): e001574
    Head trauma and environment progression of amyotrophic lateral sclerosis: long-term data from the National ALS Registry.
    Alfonso Enrique Martinez-Nunez, Jingchuan Guo, Earl Ray Dorsey, Kyle W Ruffing, James Wymer, Michael S Okun.
       Background: Environmental exposures have been linked to increased risk of amyotrophic lateral sclerosis (ALS); however, their impact on disease progression remains unclear. This study examined whether prior environmental and occupational exposures influenced functional decline in patients with an established ALS diagnosis.
    Methods: We conducted a retrospective cohort analysis using the National ALS Registry from 2010 to 2024. Participants with complete exposure histories were included. Disease progression was measured with the ALS Functional Rating Scale-Revised (ALSFRS-R) at baseline and every 3 months. Mixed-effects linear regression models assessed associations between exposures and ALSFRS-R decline, adjusting for age, sex and time since diagnosis.
    Results: The cohort included 8618 participants with ALS. The median time from diagnosis to enrolment was 2 years (IQR= 1.1-2.9), with a median of 1 year of follow-up (IQR=1-4). Exposure to herbicides (β=-0.57. IC95%=-0.86 to -0.28, p<0.001), metal dust and fumes (β=-0.28, IC95%=-0.51 to -0.04, p=0.020) and oil paint (β=-0.27, IC95%=-0.48 to -0.06, p=0.011) prior to diagnosis were each associated with accelerated decline. Head injury was associated with an overall lower ALSFRS-R score (β=-1.74, IC95%=-2.21 to -1.27, <0.001), based on our non-linear mixed effects model.
    Conclusion: Environmental and occupational exposures, particularly herbicides, metal dust/fumes and oil-based paints, were associated with faster ALS progression, and head injury was associated with overall worse function.
    Keywords:  ALS; EPIDEMIOLOGY; NEUROMUSCULAR
    DOI:  https://doi.org/10.1136/bmjno-2026-001574
  16. Ned Tijdschr Tandheelkd. 2026 May 05. 133(5): 232-238
    [A personal exploration of oral health in amyotrophic lateral sclerosis].
    M K A van Selms, F Lobbezoo, M C Verhoeff.
      Amyotrophic lateral sclerosis is a progressive neurodegenerative disease impairing motor functions, including those of the oral muscles. As a result, oral hygiene and oral care become challenging. Nonetheless, oral health in patients with amyotrophic lateral sclerosis often remains under-addressed. On the basis of interviews with Dr M.K.A. van Selms dental researcher and patient oral health in amyotrophic lateral sclerosis was explored, highlighting care, research and education. Dr van Selms identifies the neglect of oral hygiene in the care of patients with amyotrophic lateral sclerosis, and advocates for patient-informed, functionally tailored guidelines, interdisciplinary collaboration, and improved access to dental services. He also calls for ethically sensitive, patient-centred research; he stresses the relevance of inclusive training for all involved; and recommends developing instructional material for carers and patients. Dr van Selms unique perspective reveals the necessity to integrate oral health into the care for this patient group and offers starting points for improving oral health and quality of life in amyotrophic lateral sclerosis and similar diseases.
    DOI:  https://doi.org/10.5177/ntvt.2026.05.26012
  17. Ageing Res Rev. 2026 May 06. pii: S1568-1637(26)00151-0. [Epub ahead of print] 103159
    Lipid Dysregulation as a Central Contributor of Neurodegenerative Diseases: Emerging Therapeutic Targets and Strategies.
    Jiajie Zhang, Chenzhi Wang, Yanan Li, Zemeng Xiao, Zhenzhen Cai, Yuxuan Qian, Lei Shi, Qi Zhang.
      Lipid homeostasis is essential for preserving the structural integrity and functional capacity of the brain. A diverse array of lipids, including cholesterol, phospholipids, and sphingolipids, has been identified as playing pivotal roles. Dysregulation of lipid metabolism is increasingly recognized as a central pathological mechanism in neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, and Cerebrotendinous Xanthomatosis, though much of the existing evidence comes from associative studies, and causal relationships still need to be further validated through interventional studies. Here we systematically review the metabolic pathways and regulatory networks of major brain lipids, with a focus on delineating disease-specific alterations and summarizing emerging therapeutic strategies targeting lipid metabolism. These strategies encompass the modulation of cholesterol homeostasis, sphingolipid metabolism, phospholipid signaling, and fatty acid oxidation, alongside approaches that enhance lipid clearance and neural repair. Preclinical advances and ongoing clinical trials underscore the translational potential of lipid-targeted interventions. In conclusion, we emphasize the potential of lipid metabolism as a promising avenue for developing novel treatments, offering insights to guide future research and therapeutic innovation in neurodegeneration.
    Keywords:  Alzheimer's disease; Lipid metabolism; Mitochondrial dysfunction; Neurodegeneration; Neuroinflammation; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.arr.2026.103159
  18. Acta Neuropathol Commun. 2026 May 05.
    Targeting the integrated stress response or Ataxin-2 alleviates neurodegeneration in PolyGR models of C9orf72 associated frontotemporal dementia and amyotrophic lateral sclerosis.
    Nikki S Harper, Joanne L Sharpe, Jasmine Speranza, Ravinder Gulia, Jeffrey X Chen, Scott P Allen, Manpreet S Atwal, Stuart Pickering-Brown, Matthew R Livesey, Craig L Bennett, Andreas Prokop, Albert R La Spada, Ryan J H West.
      Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal, early-onset neurodegenerative diseases. The most common genetic cause of FTD and ALS is a G4C2 hexanucleotide repeat expansion in the C9orf72 gene. This mutation leads to the production of toxic dipeptide repeat proteins (DPRs), via repeat-associated non-AUG (RAN) translation. These DPRs disrupt stress granule (SG) dynamics, with SG regulators such as Ataxin-2 (ATXN2) implicated in disease risk. The integrated stress response (ISR), a key driver of SG formation via eIF2α phosphorylation, has been linked to C9orf72 expansions, but the role of individual DPRs in ISR activation remains unclear. Here, using Drosophila models expressing physiologically relevant repeat length DPRs, we identify poly(GR) as a novel activator of the ISR, inducing early and sustained eIF2α phosphorylation and SG accumulation prior to motor decline. Genetic inhibition of the ISR or knockdown of ATX2, the Drosophila orthologue of ATXN2, rescues motor deficits in these models. ATXN2 knockdown also reduces poly(GR) toxicity in mouse primary neurons. These findings position poly(GR) as a key driver of ISR activation and highlight ATXN2 and the ISR as promising therapeutic targets in C9orf72-associated FTD/ALS.
    Keywords:   Drosophila ; Amyotrophic lateral sclerosis; Ataxin-2; C9orf72; Frontotemporal dementia; Integrated stress response; Motor neurone disease; Stress granules
    DOI:  https://doi.org/10.1186/s40478-026-02301-2
  19. Neurodegener Dis Manag. 2026 May 05. 1-8
    Relationship between grip strength, functional outcome, and health-related quality of life measurements in amyotrophic lateral sclerosis patients.
    Xiaolu Liu, Dilip Dhakal, Sixin Gu, Guantong Li, Mei Jing, Gaoxiao Zhang, Yuqiang Wang, Zaijun Zhang, Dongsheng Fan.
       AIM: To explore how grip strength is related to functional status and health-related quality of life (HRQoL) in amyotrophic lateral sclerosis (ALS) patients.
    METHODS: In the phase 2 trial of TBN for treatment of ALS, 148 patients in full analysis set received TBN (600 mg or 1200 mg) or a placebo for 180 days. Outcome measurements included ALS Functional Rating Scale-Revised (ALSFRS-R), 40-item ALS Assessment Questionnaire (ALSAQ-40), grip strength, and forced vital capacity (FVC). Spearman's rank correlation was used to examine associations between grip strength, ALSFRS-R and ALSAQ-40. A principal component analysis-ANCOVA model adjusted for sex was used to further explore the associations.
    RESULTS: Grip strength was strongly correlated with ALSFRS-R fine motor function domain (rs = 0.740) and moderately correlated with ALSAQ-40 activities of daily living (ADL) domain (rs = -0.637) (p < 0.05). Weak correlations were observed between FVC and both ALSFRS-R total score (rs = 0.355) and respiratory domain (rs = 0.229) and ALSAQ-40 domains. Grip strength was a strong predictor of ALSFRS-R fine motor and ALSAQ-40 ADL domains.
    CONCLUSION: Grip strength was associated with functional status and HRQoL, supporting its potential role as a meaningful clinical outcome measure in patients with ALS.
    Keywords:  ALSAQ-40; ALSFRS-R; Amyotrophic lateral sclerosis; FVC; grip strength; tetramethylpyrazine nitrone
    DOI:  https://doi.org/10.1080/17582024.2026.2667425
  20. Muscle Nerve. 2026 May 03.
    Phosphorylated Tau at Threonine 181 Is Elevated in Amyotrophic Lateral Sclerosis Plasma.
    Tiziana Petrozziello, Evan Mizerak, Aparna Krishnamoorthy, Rachel A Donahue, Ayleen L Castillo Torres, Ranee Zara B Monsanto, Bruno L Hammerschlag, Hannah A Webster, Becky Fillingham, Pia Kivisäkk, Jamie Timmons, Kelly Fox, Steven E Arnold, Joshua Cohen, Justin Klee, Sabrina Paganoni, Merit E Cudkowicz, Lori B Chibnik, James D Berry, Ghazaleh Sadri-Vakili.
       INTRODUCTION/AIMS: Reliable biomarkers for amyotrophic lateral sclerosis (ALS) remain limited. Although previous studies have shown altered cerebrospinal fluid (CSF) tau measures in ALS, the clinical relevance of plasma tau species as biomarkers remains unclear. Here, we sought to determine whether total tau, tau phosphorylated at T181 (pTau-T181), and their ratio are altered in ALS and whether these measures correlate with disease progression.
    METHODS: Plasma samples were obtained from two independent cohorts from the Northeast ALS Consortium (NEALS) Biofluid Repository (cohort 1: n = 76 ALS and n = 52 healthy controls [HC]; cohort 2: n = 98 ALS and n = 90 HC). Cohort 1 (mean age ALS 61.8 years; 63% male) included longitudinal samples; cohort 2 (mean age ALS 45.8 years; 51% male) was cross-sectional. Tau measures were quantified using Quanterix Simoa (cohort 1) and Meso Scale Discovery (MSD) (cohort 2) platforms.
    RESULTS: In cohort 1, total tau was lower in ALS versus HC (0.88 vs. 1.49 pg/mL), whereas pTau-T181 (30.29 vs. 12.97 pg/mL) and pTau-T181:tau ratio (52.07 vs. 13.18 pg/mL) were higher. In cohort 2, total tau (40.07 vs. 25.85 pg/mL), pTau-T181 (6.77 vs. 2.18 pg/mL), and their ratio (0.37 vs. 0.098 pg/mL) were elevated in ALS. Plasma measures in cohort 1 did not correlate with decline on the revised ALS Functional Rating Scale (ALSFRS-R). Brain-derived tau (BD-tau) was elevated in ALS (10.07 vs. 5.65 pg/mL) in a subset of samples from cohort 1.
    DISCUSSION: Collectively, plasma pTau-T181 levels are consistently elevated in ALS, supporting future studies to define its potential utility as an ALS biomarker.
    Keywords:  amyotrophic lateral sclerosis; biomarker; disease progression; phosphorylated tau; tau
    DOI:  https://doi.org/10.1002/mus.70266
  21. Curr Drug Deliv. 2026 Apr 24.
    Exosomes as Advanced Nanocarriers: Overcoming the Blood-Brain Barrier for Targeted Therapeutic Delivery in Neurodegenerative Diseases.
    Farhang Aliakbari, Mehregan Rahmani, Kimia Marzookian, Narges Nasrollahi Boroujeni, Alireza Alikhanian, Fahimeh Ghasemi, Daniel E Otzen, Dina Morshedi.
       INTRODUCTION: Exosomes, nanosized extracellular vesicles secreted by diverse cell types, have emerged as promising natural nanocarriers for therapeutic delivery. Their intrinsic ability to cross the Blood-Brain Barrier (BBB) positions them as valuable tools for treating neurodegenerative diseases. This review critically examines exosome biology, transport mechanisms, engineering strategies, and their clinical potential as drug-delivery platforms for the Central Nervous System (CNS).
    METHODS: We analyzed recent experimental, translational, and clinical studies on exosomes and engineered derivatives, focusing on BBB penetration, therapeutic cargo delivery, and applications in brain disorders. Key advances and landmark preclinical studies were synthesized to provide a comprehensive perspective.
    RESULTS: Exosomes cross the BBB through receptor-mediated transcytosis, lipid raft-associated uptake, and macropinocytosis, enabling bidirectional transport between circulation and brain. Their intrinsic cargo, including proteins, nucleic acids, and lipids, can reflect disease states and serve as predictive biomarkers. Engineered exosomes further enhance delivery potential, as surface functionalization and optimized cargo loading improve brain specificity and therapeutic efficacy in preclinical models. Collectively, both native and engineered exosomes surpass many synthetic carriers in stability, targeting, and BBB penetration.
    DISCUSSION: Versus previous reviews, this manuscript integrates exosome composition, engineering, isolation technologies, and administration routes, while also addressing patent and clinical translation challenges. Importantly, it highlights quantitative and mechanistic insights into BBB transport, offering a distinct framework for advancing exosome-based CNS therapies.
    CONCLUSION: Exosomes constitute a versatile platform for BBB-crossing drug delivery. By consolidating mechanistic, preclinical, and translational evidence, this review highlights their transformative potential in neurodegenerative disease therapy while outlining limitations and future directions.
    Keywords:  Blood-brain barrier; central nervous system; drug delivery; exosomes; extracellular vesicles; nanocarrier; neurodegenerative diseases
    DOI:  https://doi.org/10.2174/0115672018430706251211094801
  22. Int J Mol Sci. 2026 Apr 14. pii: 3489. [Epub ahead of print]27(8):
    Pridopidine Protects ALS Patient-Derived Neural Progenitor Cells via Sigma-1 Receptor Activation.
    May Meltzer, Maya Shefler Zamir, Noam Tzuri, Andrew M Tan, Michal Geva, Michael R Hayden, Rachel G Lichtenstein.
      The sigma-1 receptor (S1R) is an endoplasmic reticulum (ER)-resident protein enriched at the mitochondria-associated ER membranes (MAMs) that supports ER homeostasis, preserves mitochondrial function, and enhances cell survival under stress. Disruptions of MAM integrity and prolonged ER stress are well-recognized pathological features of amyotrophic lateral sclerosis (ALS), contributing to motor neuron dysfunction and degeneration. In this study, we evaluated the protective effects of pridopidine, a highly selective and potent S1R agonist currently in clinical development for Huntington's disease (HD) and ALS, using neural progenitor cells (NPCs) derived from induced pluripotent stem cells (iPSCs) from a patient with sporadic ALS. Exposure of ALS NPCs to the ER stressor tunicamycin increased the ER stress markers binding immunoglobulin protein (BiP) and C/EBP homologous protein (CHOP), disrupted mitochondrial membrane potential, upregulated expression of the mitochondrial apoptotic marker, BAX, increased caspase-3 activation, and reduced cell viability. Pridopidine significantly attenuated tunicamycin-induced BiP and CHOP expression in a biphasic, dose-dependent manner (with maximal efficacy at 1 µM), consistent with the typical pharmacology of S1R agonists. Pridopidine restored mitochondrial membrane potential, reduced mitochondrial apoptotic signaling, shown by decreased BAX expression and caspase-3 activation, and improved survival of ALS-NPCs under ER stress. Co-treatment with the selective S1R antagonist, NE-100, attenuated these effects, supporting an S1R-mediated mechanism of action for pridopidine. Together, these results demonstrate that S1R activation by pridopidine mitigates ER-stress-induced mitochondrial dysfunction and cell loss in ALS-NPCs, resulting in enhanced survival of NPCs supporting the therapeutic potential of pridopidine in ALS.
    Keywords:  Sigma-1 receptor; amyotrophic lateral sclerosis; endoplasmic reticulum stress; iPSC-derived neural progenitor cells; mitochondria-associated membranes; mitochondrial membrane potential; pridopidine
    DOI:  https://doi.org/10.3390/ijms27083489
  23. Pharmaceutics. 2026 Apr 14. pii: 484. [Epub ahead of print]18(4):
    Intranasal vs. Device-Assisted Drug Delivery: Advantages and Limitations for the Delivery of Biopharmaceuticals to the CNS.
    Lisa Benedetta De Martini, Chiara Flora Valori, Martina Morrone, Liliana Brambilla, Daniela Rossi.
      While the Blood-Brain Barrier (BBB) is essential for the protection and function of the Central Nervous System (CNS), it also represents a challenge for drug delivery in the treatment of CNS disorders due to its limited permeability and high expression of efflux transporters. Crossing the BBB becomes even more difficult when dealing with biomolecular therapeutics (e.g., monoclonal antibodies and Antisense Oligonucleotides) due to their hydrophilic nature and high molecular weight. Over the years, different strategies have been developed in order to maximize the ability of biopharmaceuticals to cross the BBB and be delivered to the CNS. Both non-invasive techniques, mainly consisting of developing innovative vectors or using non-conventional routes of administration (e.g., intranasal delivery), and invasive methods, such as intracerebroventricular/intrathecal administration, have been tested individually and in combination. Given the improvements achieved nowadays with both approaches, here, we plan to compare the advances in invasive techniques, such as those based on the use of device-assisted strategies, and the employment of the intranasal route of administration. We are also interested in reporting the applicability of both strategies in the treatment of aggressive forms of cancer, such as glioblastoma, as well as neurodegenerative diseases, in order to determine which technique can be considered a better choice in each specific case.
    Keywords:  Nose-to-Brain administration; device-assisted delivery; drug delivery; therapy
    DOI:  https://doi.org/10.3390/pharmaceutics18040484
  24. Brain. 2026 May 08. pii: awag159. [Epub ahead of print]
    King's stages of amyotrophic lateral sclerosis: an 18F-FDG-PET study of brain connectivity.
    Francesca Di Pede, Sara Cabras, Umberto Manera, Rosario Vasta, Grazia Zocco, Emilio Minerva, Enrico Matteoni, Filippo De Mattei, Giorgio Pellegrino, Francesca Palumbo, Daniela Pascariu, Stefano Callegaro, Alessandra Maccabeo, Giulia Polverari, Alessio Martino, Alessandro Giuliani, Cristina Moglia, Andrea Calvo, Adriano Chiò, Marco Pagani, Antonio Canosa.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons. TDP-43 proteinopathy is the neuropathological signature of the disease, and 18F-FDG-PET serves as a marker of neurodegeneration in vivo. The aim of the present cross-sectional study was to disentangle 18F-FDG-PET correlates of disease severity assessed through the King's staging system, by exploring connectivity changes across motor stages. ALS patients classified as King's stage 1, 2 and 3, who underwent brain 18F-FDG-PET at diagnosis from 2008 to 2022 at the ALS Centre of Turin, were included. A multiple regression analysis to evaluate the relationship between brain metabolism and King's stage was performed. The clusters showing significant results were used as seed regions in an inter-regional correlation analysis (IRCA), performed for each stage. Out of a total of 832 ALS patients, 337 were classified as King's stage 1, 274 as stage 2, and 221 as stage 3. The three groups significantly differed in age at PET, disease duration and total ALSFRS-R score at the time of PET, C9ORF72 status, and the distribution of cognitive categories. We found a decreasing metabolic gradient from King's stage 1 to King's stage 3 in a cluster encompassing motor and cognitive areas. As King's stage increases, we found a decrease of connectivity within the sensorimotor and cognitive areas. The IRCA also showed the connectivity of motor and cognitive regions with temporal and cerebellar regions. The connectivity with temporal regions found in King's stage 1 decreases in King's stage 2 and finally disappears in King's stage 3. The connectivity with the cerebellum occurs in King's stage 2 and decreases in King's stage 3. The changes of connectivity of motor and cognitive areas with temporal and cerebellar regions among different King's stages might reflect the spread of TDP-43 proteinopathy or a compensatory mechanism, respectively. The present study suggests that 18F-FDG-PET imaging of the brain may be integrated with King's staging system to assess the extent of the pathogenic process in the context of clinical trials.
    Keywords:   18F-FDG-PET; King’s staging system; amyotrophic lateral sclerosis; connectivity
    DOI:  https://doi.org/10.1093/brain/awag159
  25. Biomedicines. 2026 Mar 26. pii: 758. [Epub ahead of print]14(4):
    Cellular Senescence in Neurodegeneration: From Cell Types to Therapeutic Opportunities.
    Marta Zawadzka, Julia Rydzek, Julia Lizon, Zuzanna Krupa, Joanna Wrona, Sławomir Woźniak.
      Neurodegenerative diseases of the central nervous system, such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, represent a growing health challenge in ageing populations. Among the mechanisms underlying these disorders, increasing attention has been directed toward the role of cellular senescence. This process, triggered by chronic cellular and oxidative stress as well as DNA damage, leads to irreversible cell-cycle arrest and the development of the senescence-associated secretory phenotype (SASP). Within the central nervous system, the accumulation of senescent cells induces chronic inflammation, blood-brain barrier disruption, and progression of neurodegenerative processes. In this review, we present current evidence regarding the mechanisms of cellular senescence in the central nervous system, with particular emphasis on the role of SASP in neuroinflammation, vascular dysfunction, and neural tissue damage. Experimental and clinical data supporting the involvement of cellular senescence in the pathogenesis of Alzheimer's disease, Parkinson's disease, and multiple sclerosis are discussed. The review also covers methods for identifying senescent cells in the brain, including molecular marker-based approaches and machine learning-based tools. Importantly, we discuss the methodological limitations of commonly used senescence markers, such as their limited specificity and the risk of false-positive detection, particularly in the heterogeneous cellular environment of the central nervous system. Strategies to improve detection reliability discussed in this review include the use of multimarker signatures, analysis of SASP components using qRT-PCR and ELISA, as well as transcriptomic approaches such as RNA sequencing and single-cell RNA sequencing. Furthermore, we analyze therapeutic strategies targeting senescent cells-senolytics, senomorphics, and SASP modulation-together with their limitations and associated clinical challenges. The collected evidence indicates that precise characterization of senescent cell populations in the brain is essential for the development of disease-modifying therapies for neurodegenerative disorders.
    Keywords:  cellular senescence; central nervous system aging; neurodegenerative diseases; neuroinflammation; senescence-associated secretory phenotype (SASP)
    DOI:  https://doi.org/10.3390/biomedicines14040758
  26. Int J Mol Sci. 2026 Apr 10. pii: 3409. [Epub ahead of print]27(8):
    Molecular Modulation of the Crosstalk Between TDP-43 and SOD1.
    Gabriela D Ribeiro, Daniela D Queiroz, José R Monteiro-Neto, Ellen Gerhardt, Gabriel F de Souza, Paola C S C Albino, Luan H Paranhos, Tiago F Outeiro, Elis C A Eleutherio.
      Glycation of superoxide dismutase 1 (SOD1) has been shown to modulate the cytosolic levels of phosphorylated TAR DNA-binding protein 43 (TDP-43), a hallmark of amyotrophic lateral sclerosis (ALS) pathology. In this study, we investigated the interaction between TDP-43 and SOD1 and assessed how methylglyoxal (MGO)-induced glycation and the ALS-associated G93A SOD1 mutation affect this interplay in H4 cells. MGO exposure reduced SOD1 activity and TDP-43 phosphorylation in cells expressing WT SOD1, but not in those expressing G93A SOD1. Both WT and mutant SOD1 interacted with TDP-43 in the nucleus and cytosol; however, cytosolic interactions were more prevalent in G93A-expressing cells. Although MGO did not significantly alter the overall interaction between TDP-43 and WT SOD1, it induced cytosolic inclusion formation at 0.4 mM, a concentration associated with reduced cell viability. These inclusions did not colocalize with stress granules, indicating alternative aggregation pathways. Treatment with cyclosporin A, which inhibits the phosphatase calcineurin, decreased both TDP-43-WT SOD1 inclusions and cytosolic interactions between TDP-43 and G93A SOD1. Together, these findings suggest that SOD1 damage, induced by glycation or ALS-linked mutation, may affect TDP-43 phosphorylation status and promote its cytosolic mislocalization and aggregation, providing new insights into ALS-associated proteinopathy.
    Keywords:  SOD1; TDP-43; amyotrophic lateral sclerosis; glycation; proteinopathy
    DOI:  https://doi.org/10.3390/ijms27083409
  27. bioRxiv. 2026 Apr 27. pii: 2026.04.23.719939. [Epub ahead of print]
    TMEM106B C-terminal fragments drive nucleocytoplasmic transport failure and TDP-43 mislocalization in the aging human brain.
    Kedamawit Tilahun, Janani Parameswaran, Myles Dudley, Daniel Pun, Fuying Ma, Jessee Zhang, Tatiana Bold, Jie Jiang.
      TMEM106B is a lysosomal membrane protein and major genetic modifier of multiple neurodegenerative diseases, including frontotemporal lobar degeneration, Alzheimer's disease, and amyotrophic lateral sclerosis. Proteolytically generated C-terminal fragments of TMEM106B assemble into amyloid fibrils that accumulate in the brains of individuals with neurodegenerative disease and in cognitively normal aged adults, yet how these fibrils produce neuronal dysfunction has remained unclear. Here, we show that cytosolic and lysosome-directed TMEM106B C-terminal fragments (CTF and gCTF) form detergent-insoluble amyloid aggregates, drive redistribution of endogenous TDP-43 from the nucleus to the cytoplasm, and accelerate neuronal death. Unbiased proximity proteomics identified the inner nuclear membrane LAP1-TorsinA axis as a fragment-specific interactome, and co-immunoprecipitation confirmed a direct physical interaction between gCTF and LAP1 that was not observed with full-length TMEM106B. Fragment expression disrupted Lamin B1 organization, mislocalized the nuclear import machinery KPNB1 and RanGAP1, and impaired importin-dependent nuclear transport in primary cortical neurons. Critically, neurons harboring endogenous TMEM106B fibrillar pathology in aged human frontal cortex exhibited the same phenotypes, namely disrupted Lamin B1 and LAP1 localization and cytoplasmic redistribution of TDP-43, whereas fibril-negative neurons from the same cases and younger control tissue retained intact nuclear envelope organization. These findings define TMEM106B proteinopathy as an upstream driver of nuclear envelope disruption and nucleocytoplasmic transport failure, linking a widespread feature of brain aging to a central mechanism of neurodegeneration.
    DOI:  https://doi.org/10.64898/2026.04.23.719939
  28. Int J Mol Sci. 2026 Apr 08. pii: 3353. [Epub ahead of print]27(8):
    Impact of Oxidative Stress-Driven Ferroptosis in Neurodegeneration.
    Asma Rafique, Aleena Junaid, Marica Bakovic.
      Ferroptosis is an iron-dependent cell death driven by lipid peroxidation and failure of cellular antioxidant defenses. It is triggered by oxidative stress and can be aggravated by aging, inflammation, and dysregulation of iron homeostasis. In the central nervous system, iron dyshomeostasis, mitochondrial dysfunction, and membrane lipid remodeling can amplify oxidative injury and increase susceptibility to ferroptotic damage, particularly in vulnerable neurons. There is growing evidence that ferroptosis-related processes are linked to Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis. This review addresses novel approaches to track ferroptosis in vivo, such as imaging and biomarker techniques, and important molecular mechanisms linking iron metabolism, reactive oxygen species, and PUFA-driven lipid peroxidation to neuronal damage. We also explore upstream transcriptional control via NRF2, iron chelation and iron-handling modulation, inhibition of lipid peroxidation, and reinforcement of the System Xc-GSH-GPX4 and CoQ10-linked defense pathways. Subsequently, we highlight translational issues that need attention to further progress ferroptosis-targeted therapies for neurodegenerative disease.
    Keywords:  GPX4; ferroptosis; iron homeostasis; lipid peroxidation; neurodegeneration; oxidative stress
    DOI:  https://doi.org/10.3390/ijms27083353
  29. iScience. 2026 May 15. 29(5): 115565
    Neuromuscular junction innervation and motor function are preserved by restoring muscarinic signaling in perisynaptic glia in ALS.
    Elsa Tremblay, Danielle Arbour, Joanne Vallée, Roberta Piovesana, Geneviève Vallières, Emine Mechichi, Richard Robitaille.
      Neuromuscular junction (NMJ) denervation is an early pathological event in amyotrophic lateral sclerosis (ALS) causing motor dysfunction and paralysis. Glial cells at the NMJ, perisynaptic Schwann cells (PSCs), ensure a balance between maintenance and repair via muscarinic receptor signaling. However, in ALS mouse models, PSCs show an aberrant muscarinic hyperactivation. We posited that this excessive activation impairs the PSC capacity to support NMJ repair in ALS. Beginning at symptoms onset, SOD1 G37R mice received daily oral administration of darifenacin, a clinically approved type 3 muscarinic receptor antagonist, to reduce PSC hyperactivation. The treatment improved locomotion and preserved NMJ innervation in male mice, with comparable effects observed in females, and extended survival in males. Functional benefits were supported by signs of glial repair and enhanced survival of lumbar motor neurons. These preclinical data indicate that pathological PSC hyperactivity contributes to NMJ denervation in ALS and support therapeutic strategies targeting NMJs in ALS.
    Keywords:  Cell biology; Molecular biology; Neuroscience; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2026.115565
  30. Life Sci. 2026 May 06. pii: S0024-3205(26)00245-6. [Epub ahead of print] 124436
    Advances in neuropharmacology: Innovative drug strategies targeting synaptic plasticity, neuroinflammation, and ion channel regulation for future CNS treatments.
    Aman Shrivastava, Shanmugapriya S Kirushnakumar, Paras Gupta, Sumeet Dwivedi, Prerna Chaturvedi, Gurmeet Singh Chhabra, Abhishek Kumar, Debashish Kumar Dey.
      As our understanding of the molecular and cellular mechanisms underlying central nervous system (CNS) disorders expands, neuropharmacology is undergoing a paradigm shift. Despite the increasing burden of neurodegenerative and neuropsychiatric diseases, challenges such as blood-brain barrier (BBB) impermeability, drug resistance, and complex pathophysiology continue to limit effective therapeutic development. This review highlights key emerging targets, including ion channel regulation, neuroinflammation, and synaptic plasticity, as important entry points for next-generation neurotherapeutics. Advances in nanotechnology and non-invasive delivery strategies are discussed for their potential to enhance brain-targeted drug delivery and address pharmacokinetic limitations. In addition, modulation of glial networks, neurotransmitter systems, and epigenetic regulators is explored as a promising therapeutic approach. Computational tools, including artificial intelligence (AI), machine learning, and in silico modelling, are increasingly used to improve target identification and support personalised treatment strategies. Furthermore, pharmacogenomics and biomarker-based approaches enable more precise and effective treatments across diverse patient populations. Emerging interventions, such as gene-modifying therapies and nanoformulated drugs, show promise for clinical application; however, challenges related to safety, scalability, and validation remain. Overall, the integration of advanced delivery systems, computational approaches, and precision medicine is driving a shift towards mechanism-based and individualised therapies, with the potential to improve outcomes in complex CNS disorders. These challenges underscore the need for advanced drug delivery strategies capable of improving brain targeting and therapeutic efficacy in CNS disorders.
    Keywords:  CNS drug delivery; Nanotechnology; Phenytoin; Sevoflurane; Synaptic plasticity
    DOI:  https://doi.org/10.1016/j.lfs.2026.124436
  31. Biomolecules. 2026 Mar 31. pii: 518. [Epub ahead of print]16(4):
    Plasma Autoantibodies Against Neurodegeneration-Related Antigens in Dementia and Elevated Chi3Li Autoantibodies in Mild Cognitive Impairment.
    Gabriela Kocurova, Zuzana Svabenska, Jan Klaschka, Ales Bartos, Jan Ricny.
      Systemic autoimmunity plays an important role in pathogenesis of neurodegenerative diseases. The objective of our study was to explore the seroprevalence of naturally occurring autoantibodies (Aabs) targeting a panel of 14 antigens broadly involved in neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, frontotemporal dementia, and vascular dementia. Commonly associated proteins with underlying neuronal pathology of the brain include amyloid-beta (Aβ), tau, alpha-synuclein (α-syn), TDP-43, and FUS. Proteins associated with glial and astrocytic involvement-TREM2 and Chi3Li; proteins related to myelin damage and axonal degeneration-light neurofilaments (NFL), myelin basic protein (MBP); synaptic loss reflected by neurogranin (NRGN), a marker of neuronal injury-neuron specific enolase (NSE); and markers of disturbed calcium homeostasis-VSNL1 and neuroinflammation-MCP-1. Presence and levels of plasma IgG against these antigens were examined using enzyme-linked immunosorbent assay (ELISA) method in patients with dementia, patients with mild cognitive impairment (MCI), and healthy age-matched controls. Aabs against all selected antigens were detected across all groups, including healthy control, with varied seroprevalence levels. For the first time, we report the presence of anti-FUS, anti-TREM2, anti-NRGN, anti-VSNL1, anti-NSE, and anti-MCP1 Aabs. Elevated anti-Chi3Li Aabs in individuals with MCI indicate a disease-associated immune signature linked to early neurodegenerative processes. Overall, these results provide evidence of systemic immune activation accompanying neurodegeneration, underscore the complexity of immune involvement, and highlight the importance of targeting multiple pathological pathways in future immunomodulatory strategies.
    Keywords:  astroglial activation; autoantibodies; dementia; fluid biomarkers; neurodegenerative diseases; neuroinflammation
    DOI:  https://doi.org/10.3390/biom16040518
  32. Front Immunol. 2026 ;17 1758356
    Resveratrol and the neuroinflammation axis in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and cerebral ischemia.
    Haoyu Wang, Fei Li, Haifan Wang, Zenan Tian, Hong Fan, Zhibin Shi.
      Resveratrol (RES), a naturally occurring polyphenolic compound found in grapes, berries, and peanuts, has attracted considerable interest because of its antioxidant, anti-inflammatory, and neuroprotective properties. This narrative review examines the current evidence regarding the potential effects of RES on memory-related processes and neuroinflammatory biomarkers in major neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and cerebral ischemia. Relevant literature was identified through searches of major scientific databases, and studies addressing the molecular mechanisms, experimental outcomes, and therapeutic implications of RES in these conditions were evaluated. The available evidence indicates that RES can modulate several biological pathways associated with neurodegeneration, including oxidative stress, inflammatory signaling, mitochondrial dysfunction, and neuronal survival. Experimental studies suggest that RES may influence key molecular mediators such as pro-inflammatory cytokines, nitric oxide (NO) signaling, and matrix metalloproteinases, which are implicated in neuronal damage and blood-brain barrier disruption. In preclinical models of AD and PD, RES has been associated with improvements in cognitive performance, reduction of neuroinflammatory markers, and attenuation of neuronal loss. Similarly, studies in MS and cerebral ischemia models indicate that RES may modulate immune responses, reduce oxidative damage, and limit ischemia-related neuronal injury. However, most of the current evidence derives from in vitro and animal studies, and clinical data remain limited. Moreover, the low bioavailability of RES and variability in dosing regimens represent important challenges for clinical translation. Therefore, although experimental findings support the potential neuroprotective role of RES, further well-designed clinical studies are required to determine its therapeutic relevance and safety in human neurological disorders. This narrative review was developed through a structured search of PubMed, Scopus, and Web of Science for articles published between 2000 and 2024, focusing on mechanistic, preclinical, and clinical investigations of RES in neurological disorders. This review synthesizes current evidence on the molecular and cellular mechanisms underlying the neuroprotective effects of RES, with particular emphasis on its antioxidant, anti-inflammatory, and immunomodulatory activities. By integrating findings from experimental and clinical research, the review highlights the potential of RES to modulate key pathways involved in neurodegeneration and neuroinflammation. Although further well-designed clinical studies are required to clarify its therapeutic efficacy and translational relevance, the available evidence supports continued investigation of RES as a promising candidate for neuroprotective strategies in neurological disorders.
    Keywords:  immune biomarkers; inflammatory; memory; neurological diseases; resveratrol
    DOI:  https://doi.org/10.3389/fimmu.2026.1758356
  33. Cell Death Dis. 2026 May 06.
    Proteasomal-dependent CHK1 degradation leads to DNA damage accumulation in ALS cellular model systems.
    Stefania Modafferi, Valentina Silenzi, Anna Garbelli, Gloria Lazoi, Eveljn Scarian, Sara D'Uva, Tiziana Santini, Adelaide Riccardi, Mauro Cozzolino, Orietta Pansarasa, Nadia D'Ambrosi, Simone Sabbioneda, Mariangela Morlando, Sofia Francia.
      Amyotrophic lateral sclerosis (ALS) is characterised by the aggregation of TDP-43 and mutant FUS in the cytoplasm of affected motor neurons. Accumulation of DNA damage is emerging as a novel correlative trait of ALS. We recently showed that formation of TDP-43 and FUS cytoplasmic inclusions (CIs) lead to DNA damage accumulation through dysregulation of the DNA damage response (DDR). However, the multiple molecular mechanisms contributing to DNA damage accumulation in affected motor neurons in ALS have not been fully elucidated. In recent years, chemical inhibition of the serine/threonine kinase CHK1 was shown to lead to accumulation of DNA breaks as well as increased apoptosis, in differentiated cortical neurons. Notably, CHK1 has been involved in DNA double-strand break repair in non-dividing cells, by acting through the histone chaperone ASF1A. In this article, we show that cells bearing FUS and TDP-43 CIs show downregulation of the protein levels of CHK1 and ASF1A. We observe CHK1 protein downregulation in neuronal cell lines, as well as in patient-derived motor neurons progenitors and in the spinal cord of a FUS-ALS mouse model. Restoration of the nuclear levels of CHK1 and ASF1A via transient overexpression, is sufficient to reduce DNA damage signal accumulation and rescues DDR defects. Importantly, we show that the ubiquitin-proteasome pathway is responsible for CHK1 degradation in cells bearing FUS CI, since its inhibition restores CHK1 and ASF1A protein levels. Our study demonstrates that proteasomal-dependent CHK1 and ASF1A downregulation contributes to accumulation of DNA damage in cells affected by ALS-linked protein aggregates.
    DOI:  https://doi.org/10.1038/s41419-026-08603-6
  34. Neuron. 2026 May 06. pii: S0896-6273(26)00321-1. [Epub ahead of print]114(9): 1537-1539
    Catching a ride: Nanoparticles bypass the blood-brain barrier.
    Senfeng Zhao, Miranda Li Xu, Wei Tao.
      Central nervous system drug delivery centers primarily on strategies aimed at crossing the blood-brain barrier. In a recent study, Gao et al.1 report that nanoparticles can bypass the blood-brain barrier by hijacking calvarial immune cells and exploiting migration through skull-meninges channels, which enables lesion-targeted, minimally invasive therapeutic delivery to the brain.
    DOI:  https://doi.org/10.1016/j.neuron.2026.04.026
  35. Microrna. 2026 Apr 23.
    Nanomedicine for Alzheimer's Disease: Diagnostic and Therapeutic Progress.
    Himani Pandey, Awaneet Kaur, Javed Khan, Anushka Sharma.
      The complex nature of the pathophysiology and limited treatment options of AD make it a huge challenge in healthcare. The recent developments in nanotechnology have given fresh hope for diagnosing and treating AD, which could serve as a way out of the existing problems. This review dwells on the role of nanotechnology in AD and its applications at its early stages through the development of nanosensors and boost imaging methods. Additionally, nanotechnology-driven therapeutic strategies are being investigated with nanoparticle-based drug delivery systems that aim to target the blood-brain barrier, among others. Current research innovations, clinical trials, and prospects highlight the transformative potential of nanotechnology in reshaping AD management. Ethical issues related to applying nanomedicine in neurodegenerative diseases, as well as fears about nanoparticles, are carefully analyzed herein. Finally, this review concludes with a synthesis of how nanotechnology has affected Alzheimer's Disease (AD) while emphasizing emerging trends and future directions toward advancing research on Alzheimer's Disease (AD). This comprehensive overview underscores the pivotal role of nanotechnology in revolutionizing AD prognosis and therapy, paving the way for personalized and effective treatment strategies.
    Keywords:  Alzheimer's disease; di-agnostic tools; nanotechnology; neurodegenerative diseases; theranostic nanoparticles; treatment strategies
    DOI:  https://doi.org/10.2174/0122115366427696260203074113
  36. Ann Clin Transl Neurol. 2026 May 04.
    Impact of Plasma p-tau181 on Cognition, Motor Phenotypes, and Disease Course in ALS.
    Elisabeth Kasper, Annaliis Lehto, Nina Nordmann, Oliver Peters, Julian Hellmann, Josef Priller, Eike Jakob Spruth, Gabor C Petzold, Ina Vogt, Patrick Weydt, Sarah Bernsen, Elisabeth Dinter, Björn Falkenburger, René Günther, Emrah Düzel, Wenzel Glanz, Matthis Synofzik, Lukas Beichert, Annika Spottke, Michael Wagner, Frederic Brosseron, Matthias C Schmid, Anja Schneider, Stefan Teipel, Johannes Prudlo, Andreas Hermann.
      Phosphorylated tau181 (p-tau181), an Alzheimer's disease biomarker, was recently evaluated in amyotrophic lateral sclerosis (ALS). We investigated plasma p-tau181 in 202 ALS/ALS-FTD patients and 94 healthy controls, assessing cognitive performance, motor function, and longitudinal dynamics. Plasma p-tau181 and NfL were significantly elevated in ALS, with p-tau181 increasing over 1 year while NfL remained stable. Neither marker correlated with cognitive performance, and only NfL was associated with disease severity and progression. Plasma p-tau181 was higher in patients with predominant lower motor neuron involvement. The results indicate that p-tau181 reflects peripheral processes in ALS, providing a complementary, mechanistically distinct biomarker from NfL.
    Keywords:  Alzheimer disease; amyotrophic lateral sclerosis; plasma p‐tau181
    DOI:  https://doi.org/10.1002/acn3.70423
  37. Neurosci Appl. 2026 ;5 106876
    Microbial tryptophan metabolites modulate blood-brain and gut barriers in vitro.
    Cristina Rosell-Cardona, Emily G Knox, Paula Sánchez-Díaz, Sarah-Jane Leigh, Emanuela Tirelli, Michael S Goodson, Nancy Kelley-Loughnane, María R Aburto, Sarah Kittel-Schneider, John F Cryan, Gerard Clarke.
      The gut microbiota influences brain function via the gut-brain axis, but the underlying molecular processes remain unclear. Critical to this communication are barrier systems, such as the epithelial gut and the blood-brain barrier, which mediate the interface between circulating signals and gut-brain communication. Microbial metabolites are key mediators of the gut microbiota that can influence barrier integrity. In this study, we used well-established in vitro models of the blood-brain and gut barriers and exposed them to a wide range of physiologically relevant stress-associated microbial metabolites, including tryptophan-derived metabolites with and without lipopolysaccharide (LPS) as a disrupting insult. We demonstrated that indole, indole-3-acetate, indole-3-propionate and tryptamine can modulate both gut and brain barriers in a dose- and cell-type dependent manner. Our findings suggest that specific indole metabolites should be further evaluated as promising novel therapeutic interventions to regulate barrier integrity along the microbiota-gut-brain axis.
    DOI:  https://doi.org/10.1016/j.nsa.2025.106876
  38. Mol Pharm. 2026 May 04.
    Estimation of Various Physiological Parameters Affecting Amyloid Plaque Distribution of a Novel MRI Contrast Agent in the Brain of Alzheimer's Disease Transgenic Mice.
    Vrishali Salian, Zengtao Wang, Geoffry Curran, Joseph F Podulso, Karunya K Kandimalla.
      Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptides as plaques in the brain parenchyma and as deposits in the cerebral vasculature. Early detection of amyloid plaques and deposits is imperative for diagnosing AD before the onset of cognitive decline. Magnetic resonance (MR) imaging using Gd (III)-based agents for contrast enhancement and plaque targeting provides a promising avenue. However, there remains a challenge due to the limited permeability of these contrast agents across the blood-brain barrier (BBB), which restricts its delivery. Furthermore, clearance mechanisms in the brain also reduce retention of contrast agents. To identify mechanisms that limit the success of contrast agents, we investigated the pharmacokinetics and the brain distribution of contrast agent, Gd[N-4ab/Q-4ab]Aβ30, using AD transgenic mouse models and compartmental modeling. Our results demonstrate that the contrast agent is internalized by parenchymal cells, which limits its availability to bind to extracellular plaques. Sensitivity analysis conducted on the compartmental model identified systemic clearance and plasma-to-brain influx as key parameters that limit the delivery of the contrast agent to the brain. The analysis also highlights the BBB as a formidable barrier for delivery and the importance of improving BBB permeability to increase the accumulation of the contrast agent in the brain. Furthermore, model simulations revealed that glymphatic drainage contributes to the poor retention and rapid elimination of the contrast agent from the brain. By elucidating the role of these biological processes and parameters, this study contributes to understanding factors limiting contrast agent efficacy in amyloid plaque imaging in the AD brain. These findings also reveal important targets for optimizing contrast agent design to improve its brain delivery.
    Keywords:  Alzheimer’s disease; Aβ; amyloid plaque; contrast agent; pharmacokinetic modeling
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.5c01565
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