bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–06–07
forty-six papers selected by
Luca Bolliger, lxBio
  1. Celebrating a breakthrough for amyotrophic lateral sclerosis.
  2. Considering prediagnostic environmental modifiers of progression in amyotrophic lateral sclerosis.
  3. Neuroprotective Effects of RNS60 in TDP-43 Pathology-Associated Amyotrophic Lateral Sclerosis.
  4. Attentional Function in Patients With Amyotrophic Lateral Sclerosis is Moderated by Age and Education.
  5. miR-146a is a pleiotropic regulator of motor neuron degeneration.
  6. Robust end-to-end stratification of amyotrophic lateral sclerosis patients via recurrent variational autoencoder and consensus clustering.
  7. The microbiota-tryptophan-brain axis in neurodegenerative diseases: pathogenic mechanisms, disease-specific roles, and translational therapeutics.
  8. Synaptic Plasticity Changes in the Somatosensory Cortex During Amyotrophic Lateral Sclerosis Progression and After Swim Training in SOD1-G93A Mice.
  9. Anti-inflammatory and immunomodulatory therapies are associated with reduced risk of age-associated neurodegenerative diseases: impact of sex and treatment duration.
  10. Fluid-based biomarkers of amyotrophic lateral sclerosis: recent advances and future prospects.
  11. Fos regulates age-dependent neuroinflammation in VAPBALS.
  12. Targeting mitophagy for neuroprotection: mechanisms and therapeutic opportunities.
  13. Multimodal analysis of cell-free DNA identifies epigenetic biomarkers for amyotrophic lateral sclerosis diagnosis and progression.
  14. Effects of fasudil on disease spreading in ALS - A MUNIX-based post-hoc analysis of the ROCK-ALS trial.
  15. The role of blood-retinal barrier in retinal neurodegenerative diseases.
  16. Ribonucleic acid as an active driver of protein aggregation in neurodegeneration.
  17. Fisetin and Neurodegeneration: From Preclinical Studies to Potential Clinical Applications.
  18. Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction.
  19. Platelet-derived extracellular vesicles as neurodegenerative disease biomarkers.
  20. The retroelement-derived human protein PEG10 is a regulator of mRNA splicing in neurons.
  21. The Unfinished Breath: Caregiver Perceptions of Terminal Events and Gaps in Amyotrophic Lateral Sclerosis Care in India.
  22. Cortical changes in amyotrophic lateral sclerosis: comparing biomarkers of glymphatic flow and cortical excitability.
  23. Molecular interplay between Non-coding RNAs and BDNF in Neurodegenerative Disorders: a systematic review.
  24. Serum neurofilaments for motoneuron and dementia diseases: a German multicenter cohort study.
  25. Distinct UNC13A Haplotype Blocks Define Disease Severity and Survival in Chinese Amyotrophic Lateral Sclerosis.
  26. Association between body composition and disease progression in adults with amyotrophic lateral sclerosis: a cross-sectional study.
  27. Reversible & Microbubble Concentration-Dependent Permeabilization of an In Vitro Human Endothelial Barrier to Small Molecules Using Ultrasound: Implications for Neurodegenerative Diseases Therapy.
  28. The gut-brain axis in Alzheimer's and Parkinson's diseases: a systematic review of microbiota-derived biomarkers and novel therapeutic approaches.
  29. TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites.
  30. Visible Tongue Fasciculations With Electromyographic Denervation in Autopsy-Proven Progressive Supranuclear Palsy Mimicking Amyotrophic Lateral Sclerosis.
  31. Overcoming the blood-brain barrier in Alzheimer's disease: translational perspectives on advanced drug delivery platforms.
  32. Induction of subtle blood-brain barrier dysfunction using preclinical diagnostic ultrasound combined with microbubbles.
  33. Peptide-Based Delivery Systems: Selected Insights into Cell-Penetrating Peptides.
  34. Compartmentalized Biomarker Correlations in HIV: Plasma-CSF Relationships Vary by Blood-Brain/Blood-CSF Barrier Permeability and Viral Suppression.
  35. Early-onset neuroinflammation drives neurodegeneration caused by lysosomal PI(3,5)P2 insufficiency.
  36. Evaluating the Role of AI Assistants in Accelerating Neurodegenerative Disease Research: Opportunities and Translational Limitations.
  37. Neurosymptomatic HIV CSF viral escape with parkinsonism and amyotrophic lateral sclerosis-like syndrome: a case report.
  38. The Relationship between Antibody-mediated Immune Responses and Four Types of Neurodegenerative Diseases: A Mendelian Randomization Analysis.
  39. Preserving blood-brain barrier properties after a metabolic insult in an in vitro model: A role for N-oleoylethanolamide supplementation.
  40. Glial fibrillary acidic protein (GFAP) in biofluids: analytical considerations and clinical relevance in neurodegenerative diseases.
  41. Therapeutic targeting of DNA repair pathway dysregulation in aging, cancer, and neurodegeneration.
  42. A Biomarker Out of Context: Understanding High p-tau217 in the Developing Brain.
  43. How does iron cross the abluminal membrane of the blood-brain barrier.
  44. Site-Specific Raman Probes Reveal Droplet Aging and Residue-Level Fibril Polymorphism in TDP-43CTD.
  45. PCSK9 in Brain Health and Disease: Liver-Vascular-Brain Interactions in Aging and Disease.
  46. Evaluation of in vitro blood-brain barrier models in central nervous system new drug development: methodological challenges and translational perspectives.
  1. Brain. 2026 Jun 03. 149(6): 1799-1800
    Celebrating a breakthrough for amyotrophic lateral sclerosis.
    Kevin Talbot.
      
    DOI:  https://doi.org/10.1093/brain/awag174
  2. BMJ Neurol Open. 2026 ;8(1): e001702
    Considering prediagnostic environmental modifiers of progression in amyotrophic lateral sclerosis.
    Christos V Chalitsios, Martin R Turner.
      
    Keywords:  ALS; EPIDEMIOLOGY; MOTOR NEURON DISEASE
    DOI:  https://doi.org/10.1136/bmjno-2026-001702
  3. Muscle Nerve. 2026 Jun 04.
    Neuroprotective Effects of RNS60 in TDP-43 Pathology-Associated Amyotrophic Lateral Sclerosis.
    Danny R Vesevick, Supurna Ghosh, Andreas Kalmes, P Hande Ozdinler, Mukesh Gautam.
       INTRODUCTION: TDP-43 pathology is broadly observed in the cerebral cortex of patients with amyotrophic lateral sclerosis (ALS). RNS60, an experimental treatment for acute ischemic stroke and ALS, enhanced mitochondrial biogenesis and function in other preclinical models. We investigated whether RNS60 improved mitochondrial stability and upper motor neuron (UMN) health in a TDP-43 mouse model of ALS.
    METHODS: prpTDP-43A315T-UeGFP mice, in which UMNs express green fluorescent protein (eGFP), and WT-UeGFP mice were treated with RNS60 or placebo intraperitoneally every other day from post-natal day (P) 30 until P90. Astrogliosis and microgliosis in brain and spinal cord were quantified by immunocytochemistry. Mitochondrial ultrastructure was studied via electron microscopy, and mitochondrial function was assessed using flow cytometry. Neuromuscular junction (NMJ) integrity was assessed in gastrocnemius, tibialis, and diaphragm muscles.
    RESULTS: RNS60 treatment reduced defective mitochondria in UMNs (prpTDP-43A315T + vehicle: 53.2% ± 0.71%; prpTDP-43A315T + RNS60: 19.6% ± 1.4%, p = 0.0001) and spinal motor neurons (prpTDP-43A315T + vehicle: 70.1% ± 0.4.48%; prpTDP-43A315T + RNS60: 33.5% ± 4.43%, p = 0.001). It increased mitochondrial membrane polarization (prpTDP-43A315T-UeGFP + vehicle: 7184 ± 1689 mean intensity; prpTDP-43A315T-UeGFP+RNS60: 22120 ± 4818 mean intensity, p = 0.032), reduced the extent of astrogliosis and microgliosis in motor cortex and spinal cord, protected UMNs compared to placebo, and enhanced the proportion of intact NMJs in leg and diaphragm muscles (prpTDP-43A315T-UeGFP + vehicle: 29.6% ± 3.6%; prpTDP-43A315T-UeGFP + RNS60: 64.3% ± 4.4%, p = 0.0002).
    DISCUSSION: These results suggest that RNS60 treatment promotes motor neuron health in ALS by protecting mitochondrial structure and function, preserving NMJ integrity, and reducing gliosis.
    DOI:  https://doi.org/10.1002/mus.70289
  4. Brain Behav. 2026 Jun;16(6): e71511
    Attentional Function in Patients With Amyotrophic Lateral Sclerosis is Moderated by Age and Education.
    Maher Zoubi, Patrick Weydt, Xenia Kobeleva.
       PURPOSE: Besides motor brain regions, amyotrophic lateral sclerosis (ALS) affects non-motor regions such as front temporal regions, affecting various cognitive domains.
    METHOD: We performed a behavioral study using the attention network test (ANT) to examine two components of attention (alerting, executive condition) and two degrees of difficulty (conflict condition) in 27 patients with ALS with no reported symptoms suggestive of cognitive impairment and 26 matched control participants.
    FINDINGS: Using a modified ANT that accounted for ALS-induced motor impairment by focusing on relative reaction times, we could demonstrate its feasibility even in severely paralyzed patients. Relative reaction time differences were comparable to controls, demonstrating the task's ability to correct for motor bias. When focusing on relative reaction times, in both groups we found intact executive and conflict effects. Furthermore, ALS patients had comparable task accuracies when reacting to congruent and incongruent easy targets. However, the task accuracy of ALS patients was significantly lower compared to controls when reacting to the incongruent hard target. This effect was enhanced by the interaction effect of ALS diagnosis and age.
    CONCLUSION: Our results suggest a significant interaction between age and ALS pathology, potentially leading to a breakdown of cognitive resources at higher levels of executive demand. We hypothesize that subclinical executive vulnerability in ALS patients becomes apparent when additional detrimental factors, such as aging, are present in patients. While we did not test co-pathologies in our cohort, co-occurring neurodegenerative or vascular processes might have contributed to this result. Our findings highlight the importance of cognitive screening for ALS patients above 60 years, even in the absence of subjective and collateral history of cognitive impairment.
    Keywords:  amyotrophic lateral sclerosis; attentional function; cognitive reserve; executive function; neuropsychology
    DOI:  https://doi.org/10.1002/brb3.71511
  5. Proc Natl Acad Sci U S A. 2026 Jun 09. 123(23): e2526314123
    miR-146a is a pleiotropic regulator of motor neuron degeneration.
    Dylan A Galloway, Hunter L Patterson, Mariah L Hoye, Tao Shen, Mark Shabsovich, Kathleen M Schoch, Cindy V Ly, Timothy M Miller.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Here, we have profiled motor neuron microRNAs (miRNAs) during motor neuron degeneration in vivo to gain a better understanding of ALS pathophysiology. We demonstrate that one miRNA, miR-146a, is downregulated in diseased motor neurons despite upregulation in bulk tissue. Genetic deletion of miR-146a significantly extended survival in SOD1G93A mice with heterozygous animals demonstrating the largest benefit. A corresponding reduction in spinal cord gliosis but not motor neuron loss was observed. Finally, we observed that a proportion of miR-146a knockout animals develop spontaneous paralysis, motor neuron loss and chronic neuroinflammation with advanced age. Together these findings demonstrate that a single miRNA influences multiple aspects of motor neuron disease and highlights the complex role for neuroinflammation in ALS pathogenesis.
    Keywords:  amyotrophic lateral sclerosis; microRNA; neuroinflammation
    DOI:  https://doi.org/10.1073/pnas.2526314123
  6. J Biomed Inform. 2026 Jun 02. pii: S1532-0464(26)00083-3. [Epub ahead of print]180 105059
    Robust end-to-end stratification of amyotrophic lateral sclerosis patients via recurrent variational autoencoder and consensus clustering.
    Federico De Mori Bajolin, Erica Tavazzi, Anna M Bianchi, Martin O Mendez.
       OBJECTIVE: This study aims to develop a data-driven methodology for stratifying Amyotrophic Lateral Sclerosis (ALS) patients based on longitudinal disease progression patterns, using a novel deep learning framework that combines a Recurrent Variational Autoencoder (RVA) with consensus clustering to identify clinically meaningful subgroups.
    METHODS: The RVA integrates Peephole Long Short-Term Memory networks within the Variational Deep Embedding (VaDE) architecture to simultaneously learn latent representations and cluster assignments from multivariate time-series data. The approach incorporates hyperparameter optimization via prediction strength with two-fold cross-validation, consensus clustering, and internal validation metrics (Silhouette Coefficient, Davies-Bouldin index, Calinski-Harabasz index) for optimal cluster selection. The methodology was validated on simulated data and applied to 3076 ALS patients from the PRO-ACT dataset, using ALSFRS-R total scores, domain subscores, and MiToS staging from the first six months of observation.
    RESULTS: Simulation experiments demonstrated that consensus clustering consistently outperformed single-model predictions across all noise levels. Applied to the PRO-ACT real data, the framework identified five distinct patient subgroups. These clusters exhibited distinct progression patterns and statistically significant differences in baseline clinical features, disease onset characteristics, and survival outcomes, with median survival ranging from 12.8 months to 27.5 months.
    CONCLUSION: The proposed deep learning framework effectively captures the heterogeneous nature of ALS progression and identifies clinically relevant patient subgroups using routine clinical assessments. The stratification provides a foundation for personalized prognosis, optimized clinical trial design, and tailored therapeutic strategies, representing a practical tool for improving ALS patient management.
    Keywords:  Amyotrophic Lateral Sclerosis; Clustering; Deep learning; Stratification; Unsupervised learning
    DOI:  https://doi.org/10.1016/j.jbi.2026.105059
  7. Front Microbiol. 2026 ;17 1820111
    The microbiota-tryptophan-brain axis in neurodegenerative diseases: pathogenic mechanisms, disease-specific roles, and translational therapeutics.
    Ziyi Wang, Lu Li, Yuhan Dong, Yamin Zhang.
      The pathogenesis of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) is very complex. Recent studies have shown that gut microbiota and their metabolites play a key role in the progression of these diseases. Tryptophan (Trp) is an essential amino acid, which mainly produces a variety of biologically active compounds in the intestine through the metabolism of indole pathway, Kynurenine pathway (KP) and serotonin pathway, including indole derivatives, Kynurenine (KYN) and serotonin (5-HT). These metabolites affect the central nervous system (CNS) through the Microbiota-gut-brain axis (MGBA) and affect CNS in a variety of mechanisms, including immune regulation, neuroprotection and maintenance of intestinal barrier function. They are involved in key pathological processes such as neuroinflammation, oxidative stress and pathological protein aggregation. This paper systematically reviews the mechanism of the role of Trp metabolites derived from gut microbiota in NDDs, and explores their specific roles in AD, PD, Amyotrophic Lateral Sclerosis (ALS) and Huntington's disease (HD), and summarizes the potential therapeutic value of the current pathway strategy. These strategies include nutritional intervention, targeted microbiome therapy [such as probiotic and fecal microbiota transplantation (FMT)], and metabolite-derived drugs. Future research must clarify its dynamic mechanism in the human body, develop relevant biomarkers, and promote personalized prevention and treatment strategies through clinical transformation, so as to provide a new direction for early intervention and treatment of NDDs.
    Keywords:  Alzheimer’s disease; Aryl hydrocarbon receptor; Microbiota-gut-brain axis; Parkinson’s disease; neurodegenerative diseases; tryptophan
    DOI:  https://doi.org/10.3389/fmicb.2026.1820111
  8. Mol Neurobiol. 2026 Jun 04. pii: 673. [Epub ahead of print]63(1):
    Synaptic Plasticity Changes in the Somatosensory Cortex During Amyotrophic Lateral Sclerosis Progression and After Swim Training in SOD1-G93A Mice.
    Anbarieh Saadat, Małgorzata Jasińska, Bartosz Cedro, Alicja Piekarska, Damian J Flis, Wiesław Ziółkowski, Elżbieta Pyza.
      Somatosensory cortex hyperexcitability is present in the pre-symptomatic stage of amyotrophic lateral sclerosis (ALS) as evidenced by brain recordings, but its synaptic basis remains unclear. We examined synaptic plasticity, the density of asymmetric (putative excitatory) and symmetric (putative inhibitory) synapses, dendritic spine morphology, and the putative excitatory/inhibitory (E/I) ratio in the B2 barrel of the somatosensory cortex in female mice of an ALS mouse model. Transgenic mice, B6SJL-Tg (SOD1*G93A)1Gur/J, were used as the ALS model, and wild-type (WT) B6SJL/F1 mice served as controls. ALS mice were allocated to experimental groups based on disease stage (pre-symptomatic, onset, or terminal) and training condition (swim-trained or untrained). Swim training was applied after the first onset of symptoms (clinical score 1). We analyzed and quantified the density of asymmetric (putative excitatory) and symmetric (putative inhibitory) synapses and E/I ratios using serial electron micrographs to understand how these parameters change during disease progression and whether swim training influences this process. Our results showed stage-dependent alterations in asymmetric (putative excitatory) and symmetric (putative inhibitory) synaptic architecture in ALS. The obtained data showed an increase in the excitatory synaptic density in the presymptomatic ALS mice. This finding is consistent with previous reports of early cortical hyperexcitability and may reflect structural alterations associated with an initial increase in excitatory synapses before disease onset. Importantly, we report here an increase in inhibitory synapses at disease onset. TEM-based synaptic density quantification revealed reduced excitatory synapse density in the B2 barrel of the somatosensory cortex of trained ALS mice compared to WT controls, alongside a trend toward a reduced putative excitatory/inhibitory synaptic ratio. However, as no significant differences were detected between trained and untrained ALS mice, the contribution of swim training to these alterations remains unclear. Notably, swim training was not associated with detectable adverse effects on somatosensory cortex ultrastructure, excitatory synapse density, or the putative excitatory/inhibitory ratio, supporting previous observations that swim training is well tolerated under these experimental conditions. To our knowledge, these results provide the first TEM-based ultrastructural characterization of synaptic architecture in swim-trained SOD1-G93A mice, although further studies are needed to establish the underlying mechanisms and therapeutic relevance in ALS.
    Keywords:  Amyotrophic lateral sclerosis; Excitatory/inhibitory ratio; Somatosensory cortex; Swim training; Synaptic plasticity; Transmission electron microscopy
    DOI:  https://doi.org/10.1007/s12035-026-05979-6
  9. Front Aging Neurosci. 2026 ;18 1818660
    Anti-inflammatory and immunomodulatory therapies are associated with reduced risk of age-associated neurodegenerative diseases: impact of sex and treatment duration.
    Helena Cortes-Flores, Georgina Torrandell-Haro, Roberta Diaz Brinton.
       Introduction: Neurodegenerative diseases (NDDs) including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and non-AD dementias share chronic neuroinflammatory mechanisms that contribute to neuronal injury and disease progression. While anti-inflammatory therapies (AITs) are associated with reduced neurodegenerative disease risk, knowledge regarding the impact of biological sex and treatment duration across multiple NDDs remains limited.
    Methods: We conducted a retrospective cohort analysis using a large propensity-score-matched population (n = 190,308; 95,154 treated vs. 95,154 untreated) to evaluate associations between long-term AIT exposure and incidence of major NDDs. Disease-specific and combined outcomes were assessed across drug classes (NSAIDs, corticosteroids, immunomodulators), sex, age, and therapy duration.
    Results: AIT exposure was associated with a significantly lower risk of developing any NDD (RR = 0.47, 95% CI 0.43-0.48, p < 0.0001) and was equally effective in both sexes. Risk reduction was observed for each age-associated disease: AD (RR = 0.40), non-AD dementia (RR = 0.51), PD (RR = 0.43), MS (RR = 0.25), and ALS (RR = 0.48). Among drug classes, immunomodulators conferred the greatest reduction (RR = 0.19), followed by corticosteroids (RR = 0.41) and NSAIDs (RR = 0.42). Duration analyses revealed a graded benefit, with RR declining from 0.94 ( < 1 year) to 0.25 ( > 6 years). Risk reduction was greatest in older participants (75-79 years).
    Discussion: Chronic use of anti-inflammatory or immunomodulatory therapies was associated with significantly reduced incidence of multiple neurodegenerative diseases in both sexes. The strongest effects were observed with immunomodulator use and prolonged therapy duration, suggesting that sustained modulation of systemic inflammation confers broad neuroprotective effects in both sexes. These findings highlight the potential of targeting immune-inflammatory pathways for neurodegenerative disease prevention and can inform prospective mechanistic and interventional studies.
    Keywords:  Alzheimer’s disease; NSAIDs; anti-inflammatory treatment; neurodegenerative disease; retrospective analysis
    DOI:  https://doi.org/10.3389/fnagi.2026.1818660
  10. Brain Res. 2026 May 29. pii: S0006-8993(26)00255-6. [Epub ahead of print]1888 150395
    Fluid-based biomarkers of amyotrophic lateral sclerosis: recent advances and future prospects.
    Yiru Jiang, Shuqi Hu, Bingjie Yang, Lingling Zhang, Ying Wang, Gaoyi Yang, Hao Zhang.
      Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with no definitive cure. The absence of specific diagnostic biomarkers leads to diagnostic delays, hindering early intervention and management. This review provides a critical appraisal of fluid-based biomarkers for ALS across multiple sources-cerebrospinal fluid (CSF), blood, urine, saliva, and tears-with emphasis on their diagnostic and prognostic potential, limitations, and readiness for clinical translation. While neurofilaments (NfL, pNfH) are well-established as sensitive indicators of neuroaxonal injury and are increasingly used as prognostic and pharmacodynamic markers in clinical trials, they lack disease specificity. Biomarkers reflecting ALS-specific pathology, such as TDP-43 species and C9orf72 dipeptide repeat proteins (DPRs), show promise but remain in early validation stages with limited multicenter data. Emerging markers from non-invasive sources (urine p75ECD, salivary chromogranin A, tear metabolomics) offer potential for repeated sampling but require rigorous external validation before clinical adoption. To address current gaps, we introduce a standardized evidence grading framework (Tier 1-3) and a comprehensive reporting template for biomarker studies, including explicit performance metrics (AUC, sensitivity, specificity, confidence intervals) and validation status. We also propose minimum reporting standards for study design, pre-analytical variables, and statistical rigor, modeled on REMARK guidelines. A roadmap for biomarker validation and a cross-fluid comparison matrix are provided to guide future research. Despite considerable progress, significant challenges remain, including biological heterogeneity, pre-analytical variability, and insufficient external validation. Future efforts should prioritize multicenter prospective studies, assay harmonization, ethical frameworks for early diagnosis, and integration of emerging technologies such as artificial intelligence and digital twins. Fluid-based biomarkers, while not yet replacing clinical evaluation, are essential tools for accelerating drug development, enabling patient stratification, and moving toward personalized medicine in ALS.
    Keywords:  Amyotrophic lateral sclerosis; Digital twin; Fluid biomarkers; Saliva; Tears; Urine
    DOI:  https://doi.org/10.1016/j.brainres.2026.150395
  11. Dis Model Mech. 2026 Jun 04. pii: dmm.052810. [Epub ahead of print]
    Fos regulates age-dependent neuroinflammation in VAPBALS.
    Namrata Pramod Kulkarni, Aparna Thulasidharan, Amarendranath Soory, Pulkit Goel, Sanhita Sarkar, Vidyadheesh Kelkar, Girish S Ratnaparkhi.
      Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor function. We have developed a Drosophila model of ALS8 (VAPBP58S) using CRISPR/Cas9 genome editing. VAPB is an ER-based adapter protein associated with and regulating intracellular membrane:membrane contact sites. VAPB P58S flies show progressive age-dependent motor deficits and a shortened lifespan, paralleling features of the human disease. VAPBP58S brains exhibit age-dependent neuroinflammation, as measured by whole-transcriptome quantitative mRNA sequencing, suggesting a broad, low-grade enhancement of signalling across multiple immune pathways (Toll, IMD, Jak-STAT, and Jun-kinase). We implicate glial cells in the brain as the site of brain inflammation and identify Drosophila Fos (Kayak) as a key modulator of age-dependent inflammation. In accordance, we find that overexpression of wild-type kayak or its dominant-active variant kayakK357R in glia reduces inflammation and, concomitantly, improves motor function. In contrast, knockdown of glial kayak accelerates age-dependent deterioration of motor function and enhances neuroinflammation. Our study underscores the roles of glial-modulated brain inflammation in dictating ALS8 progression and identifies kayak as a central negative regulator of neuroinflammation in disease.
    Keywords:  Amyotrophic Lateral Sclerosis; CRISPR/Cas9; Kayak; Neuroinflammation; Vesicle-associated membrane protein-associated protein B
    DOI:  https://doi.org/10.1242/dmm.052810
  12. NPJ Aging. 2026 Jun 03.
    Targeting mitophagy for neuroprotection: mechanisms and therapeutic opportunities.
    Jiahui Yang, Jianfeng Li, Xintong Hou, Yifei Zheng, Zeyu Zhao, Ting Zhou, Tongwei Jing, Jiming Kong, Guohui Zhang, Ying Guo.
      Mitochondria are essential for neuronal energy production, cellular homeostasis, and overall neuronal function. Due to their high metabolic demands and limited regenerative capacity, neurons are particularly vulnerable to mitochondrial dysfunction, which leads to ATP depletion, excessive reactive oxygen species (ROS) production, and calcium imbalance-ultimately causing oxidative stress, metabolic disruption, and neuronal death. Mitophagy is a selective process that removes damaged mitochondria through the autophagy-lysosome pathway. As a key mechanism of mitochondrial quality control, mitophagy preserves energy production, limits oxidative damage, and maintains mitochondrial network integrity. This process is regulated by pathways such as PINK1-Parkin and receptor-mediated mechanisms involving BNIP3 and FUNDC1, all of which help sustain cellular health by preventing mitochondrial dysfunction. Impaired mitophagy is a common feature of several neurodegenerative diseases, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and Huntington's disease, exacerbating mitochondrial damage and neuronal stress. Emerging therapeutic strategies that target mitophagy-ranging from pharmacological agents and gene therapies to dietary interventions-show promise in restoring mitochondrial quality and protecting neurons from degeneration. Nevertheless, challenges remain in translating these findings into effective clinical treatments. Mitophagy represents a critical mechanism for preserving neuronal integrity and offers a compelling target for innovative therapies against neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41514-026-00424-3
  13. J Clin Invest. 2026 Jun 01. pii: e191508. [Epub ahead of print]136(11):
    Multimodal analysis of cell-free DNA identifies epigenetic biomarkers for amyotrophic lateral sclerosis diagnosis and progression.
    Sebastian Michels, Chaorong Chen, Wolfgang P Ruf, M Madhy Garcia Garcia, Frederick J Arnold, Zhuoxing Wu, Craig L Bennett, Daniel Shams, Leslie M Thompson, Alyssa C Walker, Dennis W Dickson, Leonard Petrucelli, Johannes Dorst, Mercedes Prudencio, Wei Li, Albert R La Spada.
      The role of the epigenome in age-related neurodegenerative disorders remains understudied. Here, we analyzed circulating cell-free DNA (cfDNA) from blood to detect methylation changes as a liquid biopsy for Amyotrophic Lateral Sclerosis (ALS). Our study included 20 patients with sporadic ALS, 10 patients with C9orf72-associated ALS, 10 asymptomatic carriers of the C9orf72 repeat expansion mutation, and 21 nondisease control individuals. Following targeted enzymatic methyl-sequencing (EM-seq) of approximately 4 million CpG sites, we detected numerous differentially methylated genes, including several implicated in ALS disease risk and pathogenesis. By integrating multiple epigenetic features, we delineated a distinct epigenetic signature, which achieved an average area under the curve (AUC) of 0.91 ± 0.10 upon receiver operator characteristic (ROC) analysis, which enabled detection of approximately 70% of patients with ALS with close to 100% specificity. Furthermore, we also identified a set of genes whose methylation status significantly correlated with clinical disease progression and cerebrospinal fluid (CSF) neurofilament levels. Our results reveal the potential of cfDNA-based biomarkers to accurately diagnose ALS and potentially predict disease progression.
    Keywords:  Biomarkers; Epigenetics; Genetics; Neurodegeneration; Neuroscience
    DOI:  https://doi.org/10.1172/JCI191508
  14. Neurotherapeutics. 2026 Jun 03. pii: S1878-7479(26)00106-6. [Epub ahead of print]23(4): e00936
    Effects of fasudil on disease spreading in ALS - A MUNIX-based post-hoc analysis of the ROCK-ALS trial.
    Andreas W Wolff, Andreas Leha, Jan C Koch, Antonia F Demleitner, Christoph Neuwirth, Tim Friede, Markus Weber, Paul Lingor.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the spread of muscle weakness across body regions. ROCK-ALS was a multicenter, placebo-controlled phase 2 trial assessing the safety, tolerability, and efficacy of the Rho kinase inhibitor fasudil in ALS patients. A key exploratory objective was to evaluate fasudil's effect on the spread of muscle weakness using the Motor Unit Number Index (MUNIX), an established, quantitative electrophysiological biomarker of lower motor neuron integrity. MUNIX was assessed in 10 muscles at baseline, day 26, day 90, and day 180. In the present post-hoc analysis, correlations were assessed between baseline serum biomarkers-neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP)-and baseline clinical measures (ALSFRS-R, slow vital capacity, and MUNIX-10 sum scores) as well as their monthly rates of change, to explore potential prognostic relationships. For the analysis of disease spreading, muscles were classified as newly affected based on MUNIX decline relative to contralateral values or prior measurements, using thresholds of ≥10%, ≥20%, or ≥30%. Out of 118 participants included in the intention-to-treat population, 78 had full MUNIX datasets at baseline, and 67 had at least one follow-up. Baseline MUNIX-10 sum scores correlated with subsequent ALSFRS-R decline, suggesting prognostic value. Additionally, at day 90, fasudil significantly reduced the number of newly affected muscles compared to placebo in a dose-dependent manner over different thresholds. This supports MUNIX as a sensitive biomarker for monitoring disease spreading and demonstrates that fasudil may attenuate the progression of lower motor neuron involvement in ALS. Trial registration number: NCT03792490 (ClinicalTrials.gov); 2017-003676-31 (Eudra-CT).
    Keywords:  Amyotrophic lateral sclerosis; Disease spreading; Fasudil; MUNIX; ROCK-Inhibition
    DOI:  https://doi.org/10.1016/j.neurot.2026.e00936
  15. Am J Pathol. 2026 May 29. pii: S0002-9440(26)00159-8. [Epub ahead of print]
    The role of blood-retinal barrier in retinal neurodegenerative diseases.
    Lysander Blankenborg, Bela Anand-Apte, Saptarshi Biswas.
      Disruption of the blood-brain or blood-retinal barrier (BBB/BRB) is a common phenomenon in neurodegenerative diseases of the central nervous system (CNS). While many existing reviews focus on the link between BBB disruption and neuronal degeneration in the brain, a similar analysis of the BRB integrity in retinal degeneration is currently unavailable. Like the BBB, the inner BRB is established by retinal blood vessels encapsulated in a neurovascular unit (NVU). The retinal NVU and BRB are affected not only in retina-specific neurodegenerative diseases (e.g. diabetic retinopathy, retinitis pigmentosa etc.) but also in neurodegenerative diseases that primarily affect the brain (e.g. Alzheimer's disease, Parkinson's disease etc.). In this review, we will discuss the link between vascular abnormalities (including BRB disruption) and retinal neurodegeneration in these diseases to highlight the pivotal role of BRB integrity in neuronal homeostasis and health.
    DOI:  https://doi.org/10.1016/j.ajpath.2026.05.002
  16. Curr Opin Struct Biol. 2026 Jun 05. pii: S0959-440X(26)00080-1. [Epub ahead of print]99 103298
    Ribonucleic acid as an active driver of protein aggregation in neurodegeneration.
    Francesco A Aprile, Annalisa Pastore.
      Neurodegeneration has traditionally been largely attributed to protein aggregation, yet ribonucleic acid (RNA) has emerged as an active driver of pathology. Expanded repeat RNAs, misregulated RNA-binding proteins, and aberrant RNA-protein interactions can directly or indirectly trigger neuronal dysfunction, although the distinction between the two mechanisms might, in some cases, be loose. RNA modulates prion-like aggregation, scaffolds liquid-liquid phase separation, and either promotes or inhibits protein assembly, depending on RNA sequence and structure. The aim of this review is to discuss our current understanding of RNA's dual role-as a facilitator of aggregation or as a potential therapeutic target-revealing new mechanistic insights into diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and spinocerebellar ataxias. We highlight RNA metabolism as a central determinant of neuronal vulnerability.
    DOI:  https://doi.org/10.1016/j.sbi.2026.103298
  17. CNS Neurol Disord Drug Targets. 2026 May 22.
    Fisetin and Neurodegeneration: From Preclinical Studies to Potential Clinical Applications.
    Md Al Amin, Mehrukh Zehravi, Sherouk Hussein Sweilam, Ronald Darwin, Jeetendra Kumar Gupta, E Bhargav, G Dharmamoorthy, Voleti Vijaya Kumar, A Anka Rao, Muath Suliman, Thirunavukkarasu Periyasamy, Talha Bin Emran.
      Neurodegenerative diseases (NDs), like Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, pose significant challenges due to their gradual deterioration and limited available treatments. Fisetin, a naturally occurring flavonoid, has gained attention for its neuroprotective properties. This review explores the therapeutic potential of fisetin in NDs, focusing on its molecular processes and signaling pathways. Additionally, fisetin exhibits significant protective properties, particularly in reducing oxidative stress, neuroinflammation, and apoptosis. It enhances neuronal survival and reduces neuroinflammation by regulating key pathways, such as Nrf2/ARE, PI3K/Akt, and NF-κB. It also has anti-inflammatory, anti-apoptotic, and antioxidant actions. It stimulates autophagic processes, aiding in the removal of harmful protein aggregates, like tau tangles and amyloid plaques, which are hallmarks of NDs. Fisetin, as demonstrated through behavioral evaluations in animal models, has been found to improve motor coordination, synaptic plasticity, and cognitive function. Furthermore, fisetin's potential as a neuroprotective drug is emphasized by its role in enhancing autophagy and reducing tau and amyloid pathology. Research has shown its efficacy in enhancing neural resilience, synaptic plasticity, and cognitive function in both preclinical and in vitro settings. However, clinical translation remains limited due to challenges in pharmacokinetics and bioavailability, despite robust experimental evidence. Further clinical trials are needed to evaluate the safety and efficacy of fisetin, especially in early-stage NDs, explore potential synergistic effects, and understand the molecular interactions. The review demonstrates fisetin's therapeutic potential, recent research, and future strategies for NDs, highlighting bioavailability limitations and the need for new formulations or delivery systems.
    Keywords:  Fisetin; clinical studies.; neurodegenerative diseases; neuroprotection; oxidative stress; signaling pathways
    DOI:  https://doi.org/10.2174/0118715273427644251204045253
  18. Sci Transl Med. 2026 Jun 03. 18(852): eaeb8517
    Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction.
    Caiwei Guo, Kuchuan Chen, Sarat Vatsavayai, Tetsuya Akiyama, Chang Liu, Yi Zeng, Odilia Sianto, Edith Yang, Juliane Bombosch, Rasheen Powell, Shannon Zhen, Shila Mekhoubad, Ryan D Morrie, Georgiana Miller, Dragana Ilic, Moritz Boll, Euan Parnell, Peter Penzes, Noa Lipstein, Eric M Green, Leonard Petrucelli, William W Seeley, Aaron D Gitler.
      TAR DNA binding protein 43 (TDP-43) pathology is a defining pathological hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major feature of TDP-43 pathology is its nuclear depletion, leading to the aberrant inclusion of cryptic exons during RNA splicing. STMN2 and UNC13A have emerged as prominent TDP-43 splicing targets, but the broader impact of TDP-43-dependent cryptic splicing on neuronal function remains unclear. Here, we report previously unidentified TDP-43 splicing targets critical for membrane excitability and synaptic function, including KALRN, RAP1GAP, SYT7, and KCNQ2. Using human stem cell-derived neurons, we showed that TDP-43 reduction induces cryptic splicing and down-regulation of these genes, resulting in impaired excitability and synaptic transmission. In postmortem brains from patients with FTD, these cryptic splicing events occurred selectively in neurons with TDP-43 pathology. Suppressing individual cryptic splicing events using antisense oligonucleotides partially restored neuronal function, and combined targeting almost fully rescued the synaptic deficit caused by TDP-43 loss. Together, our findings provide evidence that cryptic splicing in these synaptic and membrane excitability genes is not only a downstream marker but instead a direct driver of neuronal dysfunction, establishing a mechanistic link between TDP-43 pathology and neurodegeneration in ALS and FTD.
    DOI:  https://doi.org/10.1126/scitranslmed.aeb8517
  19. Clin Chim Acta. 2026 Jun 01. pii: S0009-8981(26)00312-8. [Epub ahead of print] 121130
    Platelet-derived extracellular vesicles as neurodegenerative disease biomarkers.
    Safar M Alqahtani, Muhammad Afzal, Obaid Afzal, Alhumaidi Alabbas, Pradnya Phalak, Kavita Goyal.
      Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are increasingly prevalent worldwide and have not yet been adequately diagnosed, especially because they require minimally invasive, non-invasive techniques. Although established blood-based biomarkers, such as plasma p-tau217, neurofilament light chain (NfL), and GFAP, have shown clinical utility, limitations in sensitivity and scalability remain. Platelets, anucleate cytoplasmic fragments originating from megakaryocytes, are the primary producers of extracellular vesicles in the peripheral blood. These vesicles contain disease-specific cargo, including amyloid-β, α-synuclein, tau, disease-associated glycoproteins, and microRNAs (miRNAs) derived from platelets. Recent findings suggest that the cargo of platelet-derived extracellular vesicles (pEVs) may be associated with neurodegenerative changes linked to disease severity. However, validation through a prospective multicenter study is necessary. A systematic narrative review was performed by searching the PubMed, Scopus, and Web of Science databases with the keywords "platelet-derived extracellular vesicles," "platelet microvesicles," "neurodegeneration," and "biomarkers" (inception through April 2026). This review discusses the biogenesis of pEV, their composition in relation to blood markers, and their pathomechanistic roles, such as platelet-mediated blood-brain barrier disruption, neuroinflammation, and misfolded protein seeding. The diagnostic evidence of pEV-associated cargo in neurodegenerative diseases is critically evaluated and contextualized with current blood markers. Key preanalytical considerations, including the selection of anticoagulants, isolation procedures, storage conditions, and the number of freeze-thaw cycles, as well as analytical considerations, such as flow cytometric calibration, single-vesicle resolution, and multiplexed platforms, are examined for their applicability in clinical laboratory settings. The emphasis is on reporting according to the MISEV and the harmonization between laboratories. The limitations of this study are the small heterogeneous cohorts, lack of preanalytical handling standardization, ex vivo platelet activation artifact, and lack of external validation.
    Keywords:  Alzheimer's disease; Biomarkers; Blood-based biomarkers; Clinical laboratory; Neurodegeneration; Parkinson's disease; Platelet-derived extracellular vesicles; Preanalytical standardization
    DOI:  https://doi.org/10.1016/j.cca.2026.121130
  20. bioRxiv. 2026 May 24. pii: 2026.05.21.727000. [Epub ahead of print]
    The retroelement-derived human protein PEG10 is a regulator of mRNA splicing in neurons.
    A M Matthews, A M Whiteley.
      Retroelements, including retrotransposons, endogenous retroviruses, and their fragments, as well as rare co-opted or domesticated retroelements, can contribute to neurodegenerative disorders and aging through modulation of gene expression and induction of neuroinflammation. Paternally Expressed Gene 10 (PEG10) is a retroelement-derived human gene that has recently been identified as a putative driver of Amyotrophic Lateral Sclerosis (ALS) and Angelman's Syndrome. PEG10 has been reported to bind nucleic acid and undergoes a complex self-processing pathway that results in gene expression changes when the protein accumulates in cells. Here, we report that PEG10 has selectivity for binding U/G-rich RNAs and influences widespread gene expression changes. PEG10 overexpression mimics the loss of TDP-43 in broad changes to gene expression, including dysregulation of mRNA splicing pathways. Specific changes to mRNA splicing were largely unique between TDP-43 knockdown and PEG10 overexpression, as classic TDP-43 targets including STMN2 were not altered by PEG10. Instead, we identified a unique role for PEG10 in regulating splicing of neuregulin 3 (NRG3) , a ligand for the neuronal receptor ERBB4. In SH-SY5Y cells and in human neurons overexpressing PEG10, NRG3 protein levels were decreased along cellular processes, suggesting that these cells are less competent at signaling through the NRG3/ERBB4 axis. Using human patient data, we observed similar changes to NRG3 splicing in UBQLN2 -mediated ALS, where PEG10 is accumulated, as well as in some cases of sporadic ALS. In conclusion, the retroelement-derived gene PEG10 plays an unexpected role in regulating splicing of neuronal transcripts, which mimics some of the transcript changes observed in human ALS patient samples. Ultimately, this work has implications for the study of PEG10, and mRNA splicing in neurological diseases associated with elevated PEG10 abundance.
    Highlights: PEG10 NC expression influences abundance of transcripts implicated in ALS PEG10 NC expression leads to an exon skipping event in neuregulin 3 (NRG3) NRG3 expression is decreased along dendrites of PEG10 NC expressing human neuronsExpression of PEG10 NC mimics changes observed in human ALS.
    DOI:  https://doi.org/10.64898/2026.05.21.727000
  21. Ann Indian Acad Neurol. 2026 May 29.
    The Unfinished Breath: Caregiver Perceptions of Terminal Events and Gaps in Amyotrophic Lateral Sclerosis Care in India.
    Darshan Chikktimmegowda, Muddasu Suhasini Keerthipriya, Seena Vengalil, Saraswati Nashi, Dipti Baskar, J Jobi Mol, Soja Joseph, S Y Aishwarya, P B Binesha, B Dinesh Kumar, H Chandrika, Mugdha Mehta, Ajmal Roshan, Yamini Keshavaprasad Belur, Atchayaram Nalini, Priya Treesa Thomas.
       BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with a high symptom burden and limited survival. Little is known about the terminal phase experiences, symptom prevalence, and end-of-life care patterns of people with ALS (PALS) in India. This study aimed to assess terminal events and caregiver-reported outcomes in PALS to identify gaps in ALS care delivery in India.
    METHODS: A cross-sectional telephonic survey was conducted among bereaved caregivers of PALS enrolled in the Neuropalliative and Supportive Care project between December 2021 and May 2024. A structured, validated questionnaire was used to collect data on demographics, terminal-phase symptoms, medical interventions, and the nature of death as perceived by primary caregivers. Descriptive statistics and appropriate statistical analyses were performed.
    RESULTS: A total of 130 caregivers participated in the survey; the majority (57.7%) were sons or daughters. Among the 130 PALS, 76 (58.5%) were men; 56.2% had limb onset and 43.8% had bulbar onset. The mean age at death was 53.5 ± 11.4 years. Most patients (57.7%) died at home, and 29.2% experienced sudden death. Patients who died in the hospital were more likely to be on invasive mechanical ventilation ( P < 0.001). The most common terminal symptoms were breathlessness (79.2%), excessive oral secretions (54.6%), followed by anxiety or restlessness (44.6%). Only 20% received bilevel positive airway pressure, and 25.4% were on percutaneous endoscopic gastrostomy. A significant association was found between bulbar onset and assisted feeding ( P = 0.002).
    CONCLUSIONS: This study highlights the need for proactive, community-integrated palliative care services and emphasizes the urgency of early intervention and caregiver support to improve end-of-life experiences in PALS in India.
    Keywords:  Amyotrophic lateral sclerosis; end-of-life care; neuropalliative care; terminal events
    DOI:  https://doi.org/10.4103/aian.aian_1234_25
  22. Clin Neurophysiol. 2026 May 26. pii: S1388-2457(26)00449-9. [Epub ahead of print]190 2111949
    Cortical changes in amyotrophic lateral sclerosis: comparing biomarkers of glymphatic flow and cortical excitability.
    Nathan Pavey, Sicong Tu, Sheryl Foster, Nimeshan Geevasinga, Aicee Calma, Yukiko Tsuji, Matthew C Kiernan, Steve Vucic, Parvathi Menon.
       OBJECTIVE: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves a multistep process, with a central role for cortical hyperexcitability and misfolded protein accumulation. The glymphatic system mediates clearance of misfolded proteins, yet its role in modulating cortical excitability is unknown. This study aims to determine whether glymphatic dysfunction is associated with cortical hyperexcitability, thereby linking impaired protein clearance to excitotoxic neurodegeneration in ALS.
    METHODS: Glymphatic function was assessed using diffusion tensor imaging analysis along perivascular spaces (DTI-ALPS) and correlated with measures of corticomotoneuronal function assessed by transcranial magnetic stimulation (TMS). The DTI-ALPS index and cortical excitability testing were performed in 35 ALS patients and compared to 25 age-matched controls. The DTI-ALPS index was correlated with TMS and clinical measures.
    RESULTS: A significant reduction in the DTI-ALPS index was observed in ALS (p = 0.016), along with cortical hyperexcitability evident as shortened cortical silent period (CSP) duration (p = 0.001) and reduced short interval intracortical inhibition (p < 0.001). The DTI-ALPS index significantly correlated with CSP duration (R = 0.48, p = 0.027). The DTI-ALPS index was significantly reduced in ALS participants with mild functional impairment. The possibility that reduced DTI-ALPS index represents an epiphenomenon of tract degeneration cannot be completely excluded.
    CONCLUSION: This study identified a potential association between impaired glymphatic clearance and disrupted GABAB-mediated cortical inhibition, suggesting that glymphatic dysfunction may play a role in the neurodegenerative cascade in ALS.
    SIGNIFICANCE: Glymphatic dysfunction may be associated with impaired cortical inhibition, thereby contributing to cortical hyperexcitability in ALS and providing further mechanistic insight.
    Keywords:  ALS; Cortical hyperexcitability; DTI-ALPS index; Glymphatic flow
    DOI:  https://doi.org/10.1016/j.clinph.2026.2111949
  23. Mol Biol Rep. 2026 Jun 06. pii: 901. [Epub ahead of print]53(1):
    Molecular interplay between Non-coding RNAs and BDNF in Neurodegenerative Disorders: a systematic review.
    Abbas Jalaiei, Amir Hossein Kiani Darabi, Ehsan Sakkaki, Maryam Rezazadeh, Soudeh Ghafouri-Fard.
      Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays essential roles in nervous system development, neuronal maintenance, and neurogenesis. Aberrant BDNF concentrations, observed both peripherally and within the central nervous system (CNS), have been consistently implicated in the pathogenesis of a spectrum of neurodegenerative disorders (NDDs), including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and Multiple sclerosis. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), regulate gene expression and are critical factors in cellular processes relevant to neurodegenerative disease pathobiology. Consequently, ncRNAs are posited as promising biomarkers and potential therapeutic modalities for CNS-related pathologies. However, robust empirical evidence substantiating ncRNA-mediated, post-transcriptional regulation of BDNF expression in the context of neurodegeneration remains relatively scarce. The objective of this systematic review is to provide a critical synthesis of the current literature on the diagnostic and prognostic utility of ncRNAs that modulate BDNF expression, specifically within the scope of neurodegenerative disorders. Furthermore, we will explore innovative therapeutic strategies centered on targeting BDNF-associated miRNAs for the treatment of these disorders.
    Keywords:  BDNF; CNS; NcRNAs; Neurodegenerative disorder
    DOI:  https://doi.org/10.1007/s11033-026-12067-4
  24. J Neurol. 2026 Jun 02. pii: 356. [Epub ahead of print]273(6):
    Serum neurofilaments for motoneuron and dementia diseases: a German multicenter cohort study.
    Lorenzo Barba, Petra Steinacker, Steffen Halbgebauer, Patrick Oeckl, Bernhard Landwehrmeyer, Jochen Weishaupt, Federico Verde, Nicola Ticozzi, Vincenzo Silani, Johannes Levin, Sonja Schönecker, Johannes Kornhuber, Johannes Prudlo, Matthias L Schroeter, Klaus Fassbender, Klaus Fliessbach, Janine Diehl-Schmid, Holger Jahn, Martin Lauer, Johannes Dorst, Angela Rosenbohm, Samir Abu-Rumeileh, Sarah Anderl-Straub, Marie Söntgerth, Fabiola Böhm, Jens Wiltfang, Markus Otto.
       BACKGROUND: Serum neurofilament light and heavy chains (sNfL and sNfH) have been assessed as neuronal markers for amyotrophic lateral sclerosis (ALS) and dementias. Whereas sNfL has robust literature, systematic studies on sNfH are lacking. Here, we aimed to assess the diagnostic value of sNfH in comparison to sNfL in a broad range of neurodegenerative disorders.
    METHODS: We measured with immunoassays sNfH and sNfL in patients recruited in the multicenter German Frontotemporal Lobar Degeneration (FTLD) Consortium (n = 340) and in a single-center German cohort (n = 290). We assessed the diagnostic accuracy of serum biomarkers for ALS and dementia subtypes and their relationship with cognitive impairment.
    RESULTS: sNfH and sNfL were significantly increased in ALS (n = 90) vs. controls (n = 109) and ALS mimics (n = 56, p < 0.001), with sNfL showing higher discriminative accuracy (AUC = 0.94-0.95) than sNfH (AUC = 0.87-0.88). sNfH/sNfL ratio did not improve the diagnostic performance. Both markers were elevated in patients with dementia (n = 289) vs. controls (p < 0.001). sNfL was higher in behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA) and Creutzfeldt-Jakob disease (CJD) than in Alzheimer's disease (AD), whereas sNfH was similar in AD, PPA and bvFTD. sNfL, but not sNfH, was correlated with cognitive impairment at baseline and cognitive decline at follow-up in AD and bvFTD.
    CONCLUSIONS: sNfH and sNfL are elevated in motoneuron and dementia disorders. sNfH showed good discriminative accuracy for ALS, which was slightly lower than that of sNfL. sNfL, but not sNfH, showed prognostic value for assessing cognitive decline in dementia.
    Keywords:  ALS; Biomarkers; Dementia; Neurofilaments; NfL
    DOI:  https://doi.org/10.1007/s00415-026-13878-y
  25. Eur J Neurol. 2026 Jun;33(6): e70653
    Distinct UNC13A Haplotype Blocks Define Disease Severity and Survival in Chinese Amyotrophic Lateral Sclerosis.
    Cailin He, Ziqin Liu, Yanchun Yuan, Linxin Tang, Meirong Wang, Yongchao Li, Qianqian Zhao, Ling Weng, Juan Du, Hanjun Wu, Fan Hu, Renshi Xu, Jifeng Guo, Lu Shen, Beisha Tang, Junling Wang.
       BACKGROUND: UNC13A is a genetic modifier of amyotrophic lateral sclerosis (ALS) in European populations, but its role in Chinese patients remains incompletely characterized. We investigated the spectrum of UNC13A variation and its impact on disease risk and progression in a Chinese ALS cohort.
    METHODS: We performed an integrated genetic analysis of 1,533 Chinese ALS patients and 1,405 controls, including rare variant burden testing, genome-wide survival analysis, haplotype mapping, and conditional analyses. An integrated clinical-genetic prognostic score was developed and validated.
    RESULTS: Rare deleterious UNC13A variants were not associated with ALS risk. We identified two independent haplotype blocks with distinct clinical impacts. Block 1 (tagged by rs75421007) was associated with reduced baseline muscle strength (p = 0.030), while Block 2 (tagged by rs78549703), a brain-specific splicing QTL, was the primary driver of survival heterogeneity. The European variant rs12608932 showed a survival association in single-marker analysis (p = 0.024), but conditional analyses revealed its effect was not independent of Block 2. An integrated prognostic score combining clinical factors and Block 2 haplotype stratified patients into low-, intermediate-, and high-risk groups (median survival: 52.6, 37.1, and 32.0 months; p < 0.001), with decision curve analysis confirming clinical utility.
    CONCLUSIONS: This study delineates UNC13A genetic architecture in Chinese ALS, identifying two independent haplotype blocks that differentially influence disease severity and survival. The Block 2 haplotype, which includes a brain sQTL, is a major determinant of survival heterogeneity and may inform patient stratification in future studies.
    Keywords:  Chinese population; UNC13A; amyotrophic lateral sclerosis; genetic modifier; haplotype; prognostic model
    DOI:  https://doi.org/10.1111/ene.70653
  26. BMC Neurol. 2026 May 30.
    Association between body composition and disease progression in adults with amyotrophic lateral sclerosis: a cross-sectional study.
    Hamid Abbasi, Mehrnoosh Shafaatdoost, Arefeh Mohajerani, Milad Asadollahi, Maryam Rashidi, Mahsa Malekahmadi, Payam Sarraf.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration, muscle wasting, and respiratory failure, with a median survival of 30 months. Due to the strong link between dysphagia, weight loss, and disease progression, this study investigates the relationship between body composition and clinical outcomes in ALS adults. This cross-sectional study involved 93 ALS adults (29 females, 64 males) from Imam Khomeini Hospital in Tehran, selected based on EI Escorial criteria. Researchers assessed body composition, functional abilities, and disease progression using ALSFRS-R, MRC scores, and DPR, analyzing associations through linear regression models with RStudio in conjunction with R software. In this study, significant differences were found between the third and first tertiles for various measures. Significant associations were observed between body composition and ALSFRS-R for MAC (β: 3.0; P = 0.006), with underweight and moderately active adults exhibiting notable differences. The MRC score was positively associated with FFM (β: 5.8; P = 0.002), SLM (β: 5.6; P = 0.002), SMM (β: 3.8; P = 0.001), MAC (β: 3.2; P = 0.002), ICW (β: 2.7; P = 0.002), and ECW (β: 1.5; P = 0.003), while underweight and low-to-moderate physical activity adults indicated inverse associations. For DPR, significant relationships were noted for weight (β: 4.5; 95% CI: 0.02, 9.3; P = 0.002) and FFM (β: 11; P < 0.001), influenced by gender and physical activity. The findings highlight the role of gender, weight, and activity in ALS management, suggesting that maintaining a healthy weight along and muscle mass along with regular activity is associated with better outcomes. This can inform personalized treatment strategies for better patient care.
    Keywords:  Amyotrophic lateral sclerosis; Body composition; Cross-sectional; Disease progression
    DOI:  https://doi.org/10.1186/s12883-026-04971-w
  27. Mol Pharm. 2026 Jun 06.
    Reversible & Microbubble Concentration-Dependent Permeabilization of an In Vitro Human Endothelial Barrier to Small Molecules Using Ultrasound: Implications for Neurodegenerative Diseases Therapy.
    Karen Ea, Margot Pinaud, Damien Fouan, Antoine Presset, Jean-Yves Tartu, Noboru Sasaki, Nicolas Taulier, Wladimir Urbach, Christiane Contino-Pépin, Stéphane Desgranges, Hélène Blasco, Philippe Corcia, Patrick Vourc'h, Jean-Michel Escoffre.
      The blood-brain barrier (BBB) is a highly selective interface that protects the brain from circulating pathogens and toxins, but this selectivity also restricts the delivery of therapeutic agents to the central nervous system. Microbubble-assisted ultrasound (MB-assisted US) has emerged as a promising noninvasive and localized strategy to modulate BBB permeability and enhance drug delivery. This study investigated the ability of MB-assisted US to permeabilize an in vitro endothelial barrier model and promote the transport of small molecules, with particular attention to the influence of MB concentration and the reversibility of permeability changes. Immortalized human cerebral microvascular endothelial hCMEC/D3 cells were cultured on Transwell® inserts to form a confluent monolayer. Vevo MicroMarker® microbubbles were added to the apical compartment, and an US sequence (1 MHz, 1 ms PRP, 5% DC, 400 kPa PNP, 2 min) was applied. Barrier integrity and permeability were assessed using transendothelial electrical resistance (TEER), lucifer yellow (LY) permeability, and propidium iodide (PI) uptake assays. Tight junction (TJ) organization was evaluated by immunofluorescence staining of zonula occludens-1 (ZO-1) and claudin-5, and cell viability was assessed using complementary cytotoxic assays. MB-assisted US induced a significant and immediate decrease in TEER, accompanied by increased LY transport and localized PI uptake above a defined MB concentration threshold. These functional changes correlated with a reversible alteration of TJ architecture. Barrier function and TJ organization progressively returned to baseline within 24-48 h, and no cytotoxic effects were observed. Overall, these results demonstrate that MB-assisted US induces a microbubble concentration-dependent and reversible endothelial permeability to small molecules in an in vitro model, highlighting its potential for controlled drug delivery strategies targeting neurodegenerative disease.
    Keywords:  TEER; blood−brain barrier; endothelial permeability; microbubble concentration; microbubble-assisted ultrasound; neurodegenerative diseases
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.6c00168
  28. J Clin Exp Neuropsychol. 2026 Jun 02. 1-16
    The gut-brain axis in Alzheimer's and Parkinson's diseases: a systematic review of microbiota-derived biomarkers and novel therapeutic approaches.
    Vinod Kumar Singh, Prerana Gupta, Sanjeev Kumar Jain, Prithpal Singh Matreja.
       BACKGROUND: The altered gut microbiota substantially impacts the onset and progression of Alzheimer's disease (AD) and Parkinson's disease (PD), the two most widely studied neurodegenerative conditions. Microbiome-derived metabolites have been increasingly associated with disease onset, progression, and therapeutic targets in neurodegenerative disorders. Exploring the diagnostic and therapeutic implications of gut microbiome-derived biomarkers is critical to advancing our understanding and management of neurodegeneration.
    METHODOLOGY: We systematically reviewed both clinical and preclinical studies published from 2010 to 2025. Studies examining gut microbiota composition, microbial-derived metabolites, or therapeutic interventions targeting the gut microbiome were included. Identification of gut microbiome alterations, discovery of microbial or metabolite-based biomarkers, association with disease onset or progression, and/or therapeutic effects on cognitive, neurological, or inflammatory outcomes were evaluated.
    RESULT: Short-chain fatty acids(SCFAs) such as butyrate and acetate were found to be noninvasive biomarkers in patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), and Parkinson's disease (PD). Lower SCFA levels correlated with cognitive decline. Diagnostic accuracy improved when SCFA combinations were used, with AUCs ranging from 0.75 to 0.87. Trimethylamine N-oxide(TMAO) levels showed inconsistent associations, with both elevated and reduced levels linked to disease risk. Therapeutic approaches targeting gut microbiota, including probiotics, prebiotics, dietary changes, and fecal microbiota transplantation, demonstrated cognitive benefits and modulation of gut-brain signaling pathways.
    CONCLUSION: Overall, gut-derived biomarkers offer a promising avenue for early diagnosis and novel therapeutic approaches in AD and PD, while acknowledging that evidence in other neurodegenerative diseases remains limited through modulation of the gut-brain axis.
    Keywords:  Alzheimer’s disease; Gut–brain axis; Parkinson’s disease; Trimethylamine-N-oxide; gut microbiota; short-chain fatty acids
    DOI:  https://doi.org/10.1080/13803395.2026.2673084
  29. Nat Commun. 2026 Jun 05.
    TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites.
    Hannah E Ball, Abby C Woods, Yvette C Wong.
      Inter-organelle contact sites are key hubs for organelle bidirectional crosstalk. However, how mitochondria and RNA granules interact at contact sites and its regulation by mitochondrial oxidative phosphorylation (OXPHOS) remain unclear. Here, using Super-Resolution live microscopy, we identify RNA granule-mitochondria contact site formation in OXPHOS conditions. Reactive oxygen species (ROS) generated by mitochondrial OXPHOS promotes TDP-43 localization to cytoplasmic RNA granules via TDP-43 cysteine oxidation at Cys173/Cys175. Mechanistically, RNA granule-mitochondria contact tethering is mediated by TDP-43 on RNA granules binding to GADD34 on mitochondria, while contact untethering is regulated by TDP-43 oxidation. Functionally, this allows for GADD34 and its binding partner PP1 to regulate TDP-43 RNA granule dynamics, and conversely, for TDP-43 oxidation to regulate the ability of the phosphatase PP1 to form granules. Finally, disease-associated mutant TDP-43 misregulates this pathway, ultimately leading to PP1 granules lacking TDP-43. This dynamic crosstalk between TDP-43 oxidation and PP1 has significant consequences for TDP-43-associated diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).
    DOI:  https://doi.org/10.1038/s41467-026-74009-9
  30. Muscle Nerve. 2026 Jun 01.
    Visible Tongue Fasciculations With Electromyographic Denervation in Autopsy-Proven Progressive Supranuclear Palsy Mimicking Amyotrophic Lateral Sclerosis.
    Hiroyasu Inoue, Yoshihiko Horimoto, Yo Tsuda, Yuta Madokoro, Shoji Kawashima, Akio Akagi, Yasushi Iwasaki, Noriyuki Matsukawa.
      
    Keywords:  amyotrophic lateral sclerosis; progressive supranuclear palsy; tongue fasciculation
    DOI:  https://doi.org/10.1002/mus.70308
  31. Front Neurosci. 2026 ;20 1810486
    Overcoming the blood-brain barrier in Alzheimer's disease: translational perspectives on advanced drug delivery platforms.
    Napaporn Roamcharern, Ruedeemars Yubolphan.
      Alzheimer's disease (AD) is the leading cause of dementia worldwide and represents a growing public health challenge in aging societies. Despite extensive research efforts, currently approved therapies provide only limited symptomatic benefit and do not halt disease progression. A major obstacle to effective treatment is the blood-brain barrier (BBB), which severely restricts the brain delivery of most therapeutic agents. Nanoparticle-based drug delivery systems have emerged as a promising strategy to overcome BBB-related limitations by enabling precise control over physicochemical properties such as size, surface characteristics, and material composition. These properties can improve drug solubility, stability, pharmacokinetics, and targeted brain accumulation while reducing systemic toxicity. However, efficient BBB penetration and clinically feasible translation remain major challenges. This review summarizes key design principles for nanoparticles intended for AD therapy and highlights representative platforms with translational considerations, particularly lipid-based and polymer-based nanoparticles. In addition, alternative delivery strategies-including nose-to-brain nanoparticle systems and nanoparticles exploiting receptor-mediated and adsorptive-mediated transcytosis, as well as synaptic dysfunction targeting-are discussed. Collectively, this review outlines current advances and future directions for nanoparticle-mediated therapeutic delivery in AD.
    Keywords:  central nervous system delivery; nanomedicines; nanoparticles; neurodegenerative disorder; nose-to-brain delivery
    DOI:  https://doi.org/10.3389/fnins.2026.1810486
  32. Fluids Barriers CNS. 2026 Jun 02. pii: 78. [Epub ahead of print]23(1):
    Induction of subtle blood-brain barrier dysfunction using preclinical diagnostic ultrasound combined with microbubbles.
    Shakira A van der Panne, Isabella Z Koster, Anita E Grootemaat, Nicole N van der Wel, Mario G Ries, Helga E de Vries, Louise van der Weerd, Gustav J Strijkers, Erik N T P Bakker.
       BACKGROUND: The blood-brain barrier (BBB) plays a critical role in maintaining brain homeostasis by tightly regulating molecular transport. However, its integrity is often compromised with aging and in neurodegenerative diseases, contributing to disease pathology. Studying the biological consequences of BBB dysfunction independent of concomitant pathology remains challenging, largely due to the absence of reliable and inducible animal models that avoid unintended side effects such as osmotic effects, neuroinflammation, or vascular damage. In this study, we evaluated the use of Power Doppler ultrasound (PDUS) combined with microbubbles to induce widespread, bilateral BBB opening in the mouse brain.
    METHODS: Mice received intravenous infusions of SonoMAC microbubbles during transcranial PDUS application. BBB permeability was assessed via Evans Blue dye extravasation and immunofluorescence analysis of extravasated immunoglobulins. Vessel integrity was evaluated at the ultrastructural level using transmission electron microscopy (TEM).
    RESULTS: PDUS combined with microbubbles successfully induced widespread BBB opening, as evidenced by diffuse Evans Blue staining and immunoglobulin extravasation in coronal sections. Immunoglobulin leakage was detected in all analyzed brain regions, with lower levels in white matter, likely reflecting its lower vascular density. Leakage appeared to primarily originate from capillaries while TEM analysis revealed no overt vascular damage.
    CONCLUSIONS: These findings support PDUS with microbubbles as a non-destructive, reproducible method to model widespread BBB dysfunction. This approach offers an in vivo platform to study BBB-related pathophysiological processes such as impaired clearance, protein aggregation, and neurotoxicity, as well as for investigation of therapeutic delivery to the brain parenchyma.
    Keywords:  Animal mouse model; Blood-brain barrier; Immunoglobulin; Leakage; Microbubbles; Power Doppler ultrasound; Preclinical
    DOI:  https://doi.org/10.1186/s12987-026-00820-7
  33. ACS Chem Neurosci. 2026 Jun 03.
    Peptide-Based Delivery Systems: Selected Insights into Cell-Penetrating Peptides.
    Hussan Adam, Sara Abdollahi, Othman Al Musaimi.
      The blood-brain barrier (BBB) is a highly selective biological interface that regulates molecular transport between the bloodstream and the central nervous system (CNS). Its primary function is to protect the brain from harmful substances while maintaining neural homeostasis. This regulatory capacity is attributed to its complex, multilayered structure, comprising nonfenestrated endothelial cells, astrocytic end-feet, pericytes, specialized transporters, and efflux pumps, along with dynamic mechanisms that adapt to physiological changes. Despite its essential protective role, the BBB presents a significant obstacle to the delivery of therapeutics targeting CNS disorders, limiting the ability of many drugs to reach their intended sites of action. Numerous invasive and noninvasive strategies have been explored to enhance CNS drug delivery; however, many are hindered by limitations such as low efficacy, poor specificity, and immunogenicity. Peptides, as endogenous short chains of amino acids, offer a promising alternative due to their high biocompatibility, ease of synthesis, and structural versatility. Their cationic charge facilitates interactions with negatively charged proteoglycans on cell surfaces, while their amphiphilic nature enhances membrane permeability, enabling efficient cellular uptake and translocation. These properties make peptide-based vectors particularly suitable for transporting diverse therapeutic cargoes across biological barriers. This review discusses the structural characteristics, origins, and classifications of peptide vectors, as well as the mechanisms underlying their cellular internalization. It further evaluates their advantages and current limitations in clinical applications, and highlights emerging strategies aimed at optimizing peptide-mediated delivery across the BBB.
    Keywords:  CNS therapeutics; blood–brain barrier delivery; cell-penetrating peptides (CPPs); intracellular drug delivery; peptide-based nanomedicine; peptide-mediated transport
    DOI:  https://doi.org/10.1021/acschemneuro.6c00266
  34. Res Sq. 2026 May 21. pii: rs.3.rs-9418885. [Epub ahead of print]
    Compartmentalized Biomarker Correlations in HIV: Plasma-CSF Relationships Vary by Blood-Brain/Blood-CSF Barrier Permeability and Viral Suppression.
    Ronald J Ellis, Bin Tang, Patricia K Riggs, Jennifer E Ludicello, Maria Cecilia G Marcondes, Violaine Delorme-Walker, Robert K Heaton, Scott L Letendre.
       BACKGROUND: Neuroinflammation is common in people with HIV (PWH) and may be reflected also in plasma biomarkers; the latter are sometimes used as surrogates for CSF. However, use of plasma biomarkers in this way risks obscuring compartment-specific processes since distribution across the blood-brain barrier (BBB) varies between proteins with some reaching the CNS more readily than others. We tested the hypothesis that BBB and viral suppression status shape cross-compartment biomarker coupling, clarifying when plasma proteins do or do not represent neuroinflammation.
    METHODS: Paired CSF and plasma samples from 567 PWH in the CHARTER cohort were analyzed with the Olink Target-96 Inflammation Panel. Using regression, canonical correlation, and machine learning, we evaluated viral suppression and BBB permeability (indexed by CSF total protein levels, which are more readily available clinically and highly correlated with the CSF to serum albumin ratio) as effect modifiers of CSF-plasma biomarker correlations.
    RESULTS: Intra-CSF and intra-plasma correlations were consistently strong, but cross-compartment correlations were weak and inconsistent. Some proteins had strong correlations when CSF total protein was high, including CD8A, IL-12B, TNFRSF9, and TNFB. Unsuppressed viremia amplified broader cross-compartment signaling (e.g., IL-12B, CXCL9, CXCL10).
    CONCLUSIONS: BBB permeability and viral suppression moderate biomarker compartmentalization in PWH. These findings support a hypothesis-driven framework in which biomarkers can be classified as CNS-restricted, peripherally driven, or BBB-dependent. This mechanistic structure informs biomarker selection for clinical trials and provides testable models of neuroinflammation in PWH.
    DOI:  https://doi.org/10.21203/rs.3.rs-9418885/v1
  35. Neurobiol Dis. 2026 Jun 03. pii: S0969-9961(26)00212-3. [Epub ahead of print] 107467
    Early-onset neuroinflammation drives neurodegeneration caused by lysosomal PI(3,5)P2 insufficiency.
    Bridget Wong, Morgan Payne, Alexander Silva, Emma Kurniawan, Alison S Eidman, Donald Pizzo, Rachana Rajupalem, Guy M Lenk, Joao A Paulo, Taimur Khan, Eeva-Liisa Eskelinen, Steve P Gygi, Nicholas G Brown, Miriam H Meisler, Andrew S Mendiola, Brandon M Gassaway, Cole J Ferguson.
      Phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] is a lysosomal signaling lipid whose deficiency, caused by mutations in the PIKfyve complex subunits Fig. 4 or VAC14, underlies a spectrum of fatal neurologic diseases including Charcot-Marie-Tooth type 4 J (CMT4J) and amyotrophic lateral sclerosis (ALS). To map the molecular consequences of PI(3,5)P2 insufficiency in the brain, we performed quantitative proteomic and transcriptomic analyses of three mouse lines bearing distinct loss-of-function mutations in Fig. 4 or Vac14, examining the brain at the presymptomatic and end stages. Strikingly, profound neuroinflammation was already present at postnatal day 5 (before significant neurodegeneration), characterized by complement activation, interferon signaling, and parenchymal infiltration of peripheral myeloid cells and T-cells. Isolated mutant microglia exhibited a markedly pro-oxidative transcriptional state with elevated reactive oxygen species, a partly non-cell-autonomous phenotype, being present in microglia from mice with conditional Fig. 4 inactivation in just neurons and astrocytes. Comparison of early (P5) and late (P25) proteomics data revealed that PI(3,5)P2 insufficiency impairs developmental remodeling of the brain proteome: proteins typically upregulated during postnatal maturation failed to accumulate, implicating lysosomal function in neurodevelopment. We identify coordinated elevation of p53, Fas receptor, inflammatory caspases, Gasdermin D, RIPK1, and ZBP1, consistent with multifactorial inflammatory cell death with features of apoptosis, pyroptosis, and necroptosis. Many of the dysregulated proteins are encoded by genes mutated in lysosomal storage disorders, ALS, CMT, Alzheimer's and Parkinson diseases, extending the pathogenic relevance of PI(3,5)P2 insufficiency. Together, these findings establish that early neuroinflammation is a defining - and likely initiating - feature of neurodegeneration caused by disruption of lysosomal PI(3,5)P2.
    Keywords:  Astrocyte; Fas; Fig4; Lysosome; Microglia; Neuroinflammation; PI(3,5)P2; PIKfyve; Phosphoinositide; Reactive oxygen species; Vac14; cGAS-STING; p53
    DOI:  https://doi.org/10.1016/j.nbd.2026.107467
  36. Neuropsychiatr Dis Treat. 2026 ;22 614952
    Evaluating the Role of AI Assistants in Accelerating Neurodegenerative Disease Research: Opportunities and Translational Limitations.
    Xiyue Yu, Qianqian Yao.
      Neurodegenerative diseases including Alzheimer's disease and Parkinson's disease remain among the most challenging disorders to study, diagnose and treat. Despite rising prevalence with population aging, disease-modifying therapies remain scarce and research progress is hindered by biological complexity, patient heterogeneity, and incomplete experimental systems. Artificial intelligence (AI) has emerged as a transformative approach given the high-dimensional and multimodal data generated in this field. Traditional machine learning and deep learning have advanced imaging biomarker detection, disease trajectory prediction, drug target prioritization, and clinical data mining. More recently, foundation models and large language models (LLMs) have expanded AI from task-specific prediction tools to versatile assistants supporting literature retrieval, summarization, coding, data interpretation, and hypothesis generation. Although AI assistants promise to accelerate research workflows, their outputs are prone to dataset biases, poor interpretability, distribution shift, and hallucinations, which are particularly problematic in neurodegenerative research given subtle phenotypic variations, imperfect labeling, and protracted disease courses. This review evaluates the current applications of AI in neurodegenerative disease research, including drug discovery, biomarker identification, and multi-omics integration. We then discuss the transition from analytical AI models to general-purpose AI assistants and their potential to streamline scientific workflows. Critical limitations including bias, interpretability, reproducibility, and LLM hallucinations are highlighted, alongside ethical, regulatory and practical challenges. We argue that the most sustainable near-term model is human-AI collaboration rather than fully autonomous research, with its primary focus placed on research rather than clinical practice. Meaningful acceleration requires rigorous validation, transparent usage, and expert oversight to preserve scientific rigor and translational relevance.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; artificial intelligence; neurodegenerative diseases
    DOI:  https://doi.org/10.2147/NDT.S614952
  37. J Neuroimmunol. 2026 May 28. pii: S0165-5728(26)00140-2. [Epub ahead of print]418 578992
    Neurosymptomatic HIV CSF viral escape with parkinsonism and amyotrophic lateral sclerosis-like syndrome: a case report.
    Francesca Bridge, Wesley Thevathasan, David Schultz, WenWen Zhang, Edwina Wright, Wei Zhen Yeh.
      Human immunodeficiency virus (HIV) infection can lead to various neurologic complications affecting central and peripheral nervous systems. Rarely, patients on combined anti-retroviral therapy (CART) with peripheral virologic suppression may develop compartmentalised central nervous system infection with cerebrospinal fluid (CSF) viral escape. We report the case of a 42-year-old man with chronic HIV infection and a previous diagnosis of Parkinson's disease referred for neurologic evaluation with diffuse hyperreflexia including brisk jaw jerk. He was adherent to combined anti-retroviral therapy (CART). During follow-up, he developed mild upper and lower limb weakness and gait instability. Electromyography was consistent with a motor neuropathy or neuronopathy. Neuraxial MRI showed non-specific supratentorial white matter lesions. Plasma HIV viral load was suppressed (<20 copies/mL) whereas CSF viral load was 35 copies/mL, consistent with CSF viral escape. CSF neopterin level was elevated indicating neuroinflammation. HIV-associated neurological overlap syndrome, with parkinsonism and an amyotrophic lateral sclerosis-like syndrome, in the context of neurosymptomatic CSF escape was diagnosed. The patient's HIV CART regime was adjusted to improve CNS penetration. Neurosymptomatic HIV CSF escape is a rare and likely under-recognised complication which can occur despite compliance with CART. When suspected, CSF viral load should be tested. CART optimisation to improve CNS penetration may be potentially beneficial in neurosymptomatic CSF viral escape and to reduce HIV-associated neurotoxicity, but these require further study to confirm.
    Keywords:  Amyotrophic lateral sclerosis-like syndrome; CSF escape; Cerebrospinal fluid; HIV; Human immunodeficiency virus; Neurological; Parkinsonism
    DOI:  https://doi.org/10.1016/j.jneuroim.2026.578992
  38. Comb Chem High Throughput Screen. 2026 May 20.
    The Relationship between Antibody-mediated Immune Responses and Four Types of Neurodegenerative Diseases: A Mendelian Randomization Analysis.
    Jinjian Li, Chunshu Rong, Zhen Wei, Xu Wang, Dexi Zhao.
       INTRODUCTION: Recognizing the risk factors associated with neurodegenerative diseases is essential for their prevention. Currently, no studies are exploring the causal link between antibody-mediated immune responses and neurodegenerative diseases. This Mendelian randomization (MR) study further examines whether a causal relationship exists between antibodymediated immune responses and neurodegenerative diseases, and offers evidence supporting causality.
    METHOD: Data on antibody-mediated immune responses came from this study, which selected 9,724 subjects as the subgroup research participants and collected their serum samples for microbiological serological analysis. The large artery atherosclerotic stroke data includes 4,373 patients. The multiple sclerosis consists of 1,683 cases. Parkinson's disease comprises 37,688 cases. Alzheimer's disease includes 17,008 cases. MR analysis was conducted to estimate the associations between antibody-mediated immune responses(exposure) and neurodegenerative diseases(outcome) risk.
    RESULT: The IVW analysis revealed that 9 antibody-mediated immune responses were associated with 4 neurodegenerative diseases, including anti-varicella-zoster virus and Epstein-Barr virus antibodies, and others.
    DISCUSSION: This study systematically investigates, for the first time through Mendelian randomization analysis, the potential relationships between antibody-mediated immune responses and various neurodegenerative diseases. The results indicate that a total of 9 antibody-mediated immune responses are significantly associated with the risk of four neurodegenerative diseases: Conclusion: These antibody-mediated immune responses serve as potential markers for predicting the occurrence and development of neurodegenerative diseases. Our genetic analysis suggests that antibodies against antigens may be involved in the pathological process of neurodegenerative diseases, which provides a new direction for future exploration of their specific mechanisms.
    Keywords:  Mendelian randomization; antibody-mediated immune responses; epstein-barr virus.; genome-wide association studies; varicella-zoster virus
    DOI:  https://doi.org/10.2174/0113862073448107260325213324
  39. Biochem Pharmacol. 2026 Jun 04. pii: S0006-2952(26)00472-7. [Epub ahead of print] 118137
    Preserving blood-brain barrier properties after a metabolic insult in an in vitro model: A role for N-oleoylethanolamide supplementation.
    Simona Federica Spampinato, Lara Capitani, Leonardo Camillò, Enrica Marzani, Stefania Vigliermo, Antonio Santoro, Valentina Bordano, Luigi Sebastiano Battaglia, Elisa Benetti.
      High consumption of saturated fatty acid drives to a condition of low-grade inflammation, also involving the central nervous system (CNS). The blood-brain barrier (BBB), being the interface between the periphery and the brain, can represent an important target in preventing such CNS damage. N-oleoylethanolamide (OEA), whose production is inhibited by a high fat diet, is an endocannabinoid-like lipid that induces satiety, but can also counteract diet associated-inflammation. Here, we simulated in an in vitro BBB model the damage subsequent a metabolic insult and explored the effects of OEA supplementation on it. The metabolic insult was induced by treating the different components of the neurovascular unit, endothelial cells, astrocytes and microglia, with the combination of lipopolysaccharide (LPS, 100 ng/ml) and the saturated fatty acid palmitic acid (PA, 250 μM). The insult was responsible for microglial and astrocytic inflammatory response, as well as for the increase of barrier permeability observed in endothelial/astrocytes co-cultures. OEA (25 μM) supplementation prevented endothelial permeability, due to the stabilization of the junctional protein claudin-5 at the cellular boundaries. Such an effect was mediated by the modulation of the peroxisome proliferator-activated receptor alpha (PPAR-α), since PPAR-α antagonist GW6741 (10 μM) blunted it. OEA-induced gene expression of claudin-5 in endothelial cells and, indirectly acting on astrocytes, prevented matrix metalloprotease-2 (MMP2) release, which, in turn, contributed to BBB integrity. Given that dietary fat overconsumption suppresses OEA biosynthesis, its external supplementation may be beneficial, since it could restore brain reward circuits and satiety, and improve BBB stability, thus reducing the occurrence of neuroinflammation, often observed in metabolic disorders.
    Keywords:  Astrocytes; Endothelial cells; GW6741; Microglia; PPAR-α; Palmitic acid
    DOI:  https://doi.org/10.1016/j.bcp.2026.118137
  40. J Neurol. 2026 Jun 01. pii: 351. [Epub ahead of print]273(6):
    Glial fibrillary acidic protein (GFAP) in biofluids: analytical considerations and clinical relevance in neurodegenerative diseases.
    Aurélie Hanin, Isabelle Quadrio, Jean-Louis Beaudeux, Foudil Lamari.
      For many years, astrocytes were viewed mainly as supportive cells, responding passively to neuronal injury. Over the last decade, this perspective has changed substantially, and astrocytes are now shown to be highly dynamic cells that actively shape neurodegenerative processes. As a result, interest has grown in biomarkers capable of capturing astrocytic activity in vivo. Glial fibrillary acidic protein (GFAP), an intermediate filament protein predominantly expressed by astrocytes, is released into cerebrospinal fluid and blood during astrogliosis and can be reliably measured using ultrasensitive immunoassays. Increasing evidence indicates that GFAP levels are elevated across several neurodegenerative diseases and reflect both disease presence and severity. In Alzheimer's disease, blood GFAP rises early in the disease course, often before overt cognitive decline, and is closely associated with amyloid pathology and subsequent progression. In Lewy body dementia and Parkinson's disease, GFAP provides complementary information by reflecting astroglial activation, identifying patients with concomitant Alzheimer's pathology, and capturing disease heterogeneity. In frontotemporal dementia, GFAP levels are consistently increased and correlate with disease severity, particularly in genetic forms, although disease specificity remains limited. Beyond its diagnostic value, GFAP holds promise as a prognostic and pharmacodynamic biomarker, supporting patient stratification and monitoring in clinical trials. However, its clinical interpretation requires careful consideration of analytical methods, pre-analytical conditions, age-related effects, and systemic confounders. Overall, GFAP has emerged as a valuable marker of astrocytic involvement in neurodegeneration and represents an important component of future multimodal biomarker strategies aimed at improving precision medicine in neurology.
    Keywords:  Diagnosis; GFAP; Neurodegenerative diseases; Prediction; Prognosis
    DOI:  https://doi.org/10.1007/s00415-026-13896-w
  41. Expert Opin Ther Targets. 2026 Jun 02.
    Therapeutic targeting of DNA repair pathway dysregulation in aging, cancer, and neurodegeneration.
    Vipin Kumar, Mohmmad Kashif, Vivek Singh, Rahul Singh Rawat, Aamir Khan, Gautam Chandra Sarkar, Misba Majood.
       INTRODUCTION: Genome maintenance is increasingly recognized as a shared vulnerability across aging, cancer, and neurodegeneration, yet the therapeutic implications of pathway-specific dysregulation of DNA repair remain incompletely defined.
    AREAS COVERED: This review integrates recent mechanistic and translational literature on how base excision repair, nucleotide excision repair, mismatch repair, homologous recombination, canonical non-homologous end joining, and alternative end joining are remodeled across these conditions. We discuss how oxidative stress, replication stress, telomere dysfunction, mitochondrial injury, and persistent DNA damage response signaling drive senescence and inflammation; how tumor cells exploit repair rewiring to survive genotoxic stress and acquire resistance; and how post-mitotic neurons are limited by restricted repair redundancy. We also summarize biomarkers for repair-state stratification and emerging strategies targeting PARP, ATR, ATM, DNA-PK, POLQ, and cGAS-STING.
    EXPERT OPINION: Clinical translation will depend less on single-gene alterations than on defining context-specific repair states and pathway dependencies. Such stratification should enable rational combinations that either restore repair fidelity in aging and neurodegeneration or exploit repair addiction in cancer.
    Keywords:  Alzheimer’s disease (AD); And Huntington’s disease (HD); DNA damage and repair; Parkinson’s disease (PD); aging; amyotrophic lateral sclerosis (ALS); cancer; genomic instability; homologous recombination; neurodegenerative diseases; non-homologous end joining
    DOI:  https://doi.org/10.1080/14728222.2026.2683686
  42. Mol Neurobiol. 2026 Jun 02. pii: 667. [Epub ahead of print]63(1):
    A Biomarker Out of Context: Understanding High p-tau217 in the Developing Brain.
    Akansha Pal, Himanshu Yadav, Deepak Yadav, Falguni Goel, Mithun Singh Rajput.
      Phosphorylated tau at threonine 217 (p-tau217) is generally considered a very specific biomarker of Alzheimer's disease and tau-mediated neurodegeneration in adult patients, where its increase is strongly associated with amyloid, pathology, synaptic dysfunction, and progressive cognitive decline. However, surprisingly, some data report extremely elevated levels of p-tau217 in plasma and cerebrospinal fluid of healthy neonates and infants, i.e., without the presence of neurodegeneration, cognitive impairment, or structural brain damage. The latter paradoxical situation raises a fundamental question that might literally rewrite the interpretations about the tau phosphorylation being a strictly pathological process. This overview aims to bring together the latest clinical, biochemical, and developmental neuroscience literature to unveil the physiological function of p-tau217 during early brain development. We argue that high p-tau217 in infancy may be indicative of ongoing neurodevelopmental processes, such as axonal growth, synaptogenesis, neuronal plasticity, and cytoskeletal remodeling, rather than tau toxicity. Further, we analyze the contribution of the differential expression of tau isoforms, phosphorylation rates, clearance pathways, and BBB permeability in development that could explain the age-dependent biomarker profiles. In addition, this review compares the biology of tau in neonates and adults in a detailed manner, explaining how the context-dependent regulation of tau phosphorylation distinguishes p-tau217 as a developmental marker or a pathological marker. Grasping this difference is essential for the correct reading of tau biomarkers throughout the life span and for preventing the neurodegenerative risk in children from being wrongly diagnosed. In the end, this paradox highlights the need for biomarker frameworks that are specific to different ages and offers new understandings of tau physiology that might lead to novel therapies for tauopathies in the future.
    Keywords:  Babies; Biomarker; Brain damage; P-tau217
    DOI:  https://doi.org/10.1007/s12035-026-05968-9
  43. Exp Mol Med. 2026 Jun 03.
    How does iron cross the abluminal membrane of the blood-brain barrier.
    Qian Guo, Tianying Wang, Zhong-Ming Qian, Christopher Qian.
      The process of iron transport across the blood-brain barrier (BBB) includes two transmembrane steps: step 1, iron in circulating blood first passes through the luminal membrane (blood side) of BBB cells; step 2, it then passes through the abluminal membrane of the cell (cerebroside) and eventually enters the brain. Compared with step 1, we know relatively little about the mechanism of step 2. However, a large number of studies conducted in the past two decades since the discovery of ferroportin 1 (Fpn1) in 2000 has greatly enhanced our understanding of this issue. Accumulating evidence suggests that Fpn1 is a key player in step 2 and that Fpn1/hephaestin and/or Fpn1/ceruloplasmin iron export pathways found in the basement membrane of intestinal enterocytes have the same role in step 2. In this Review, we focus on the current understanding of the role of Fpn1 in iron transport across the abluminal membrane of the BBB.
    DOI:  https://doi.org/10.1038/s12276-026-01734-y
  44. J Am Chem Soc. 2026 Jun 02.
    Site-Specific Raman Probes Reveal Droplet Aging and Residue-Level Fibril Polymorphism in TDP-43CTD.
    Matthew D Watson, Jennifer C Lee.
      The C-terminal domain of TAR DNA-binding protein 43 (TDP-43CTD) drives both liquid-liquid phase separation (LLPS) and amyloid formation. Understanding how TDP-43CTD droplets convert into amyloid aggregates, a process implicated in amyotrophic lateral sclerosis and frontotemporal dementia, requires methodology capable of site-specific structural characterization with spatial resolution. Here, we used confocal Raman spectroscopy in conjunction with an alkyne-modified amino acid (4-ethynyl-l-phenylalanine, FCC) to probe aging in individual TDP-43CTD droplets at seven aromatic sites. While nascent droplets are composed of disordered proteins, β-sheet conformers develop in aged droplets and amyloid aggregates. All three states are spectrally distinct via the alkyne stretching band, with sensitivity that varies depending on the aromatic site probed. C-terminal sites (Y374FCC, W385FCC, and F397FCC) are highly sensitive amyloid probes, revealing multiple polymorphs at the single-residue level that are not resolvable by global secondary structure or morphological characterization alone. Strikingly, while W334FCC abolishes β-sheet formation in droplets, de novo aggregation still occurs, demonstrating that droplet aging is not required for amyloid formation. Given its broad applicability to other proteins and compatibility with cellular imaging, this work establishes a generalizable approach for investigating conformational changes underlying LLPS and amyloid formation in cellulo.
    DOI:  https://doi.org/10.1021/jacs.6c07727
  45. Aging Dis. 2026 May 22.
    PCSK9 in Brain Health and Disease: Liver-Vascular-Brain Interactions in Aging and Disease.
    Mengqi Zhang, Neel S Singhal.
      Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of peripheral cholesterol metabolism. Inhibitors of hepatic PCSK9 potently reduce low-density lipoprotein cholesterol (LDL-C) and have become a staple of lipid-lowering therapeutic regimens for patients with atherosclerotic cardiovascular disease. Although the role of PCSK9 in the central nervous system (CNS) is less well-defined, accumulating evidence suggests that it modulates CNS cholesterol homeostasis and responses to injury, neuroinflammation, and amyloid-β and tau protein deposition. Thus, peripheral and central PCSK9 molecular actions have important pathophysiological consequences for aging, cerebrovascular disease, and neurodegenerative disease. In this review, we summarize PCSK9 functions in the context of the liver-vascular-brain axis and examine mechanistic and therapeutic links in PCSK9 biology and neurological diseases. By integrating insights from preclinical and clinical research, we highlight the current state of knowledge regarding the potential relevance of PCSK9-inhibiting therapies in brain health and disease. Given the remarkable lipid-lowering effects of PCSK9 inhibitors, advancing our understanding of the multi-organ interactions influenced by PCSK9 may inform future therapeutic strategies, although clinical evidence supporting neurological benefit currently remains limited.
    DOI:  https://doi.org/10.14336/AD.2026.0209
  46. Expert Opin Drug Deliv. 2026 Jun 02. 1-15
    Evaluation of in vitro blood-brain barrier models in central nervous system new drug development: methodological challenges and translational perspectives.
    Chang-Uk Lee, Dan Bi Park, Eunyoung Lee, Seung Joon Kim, Yu-Jeong Seong, Yongki Hwang, Hyobin Won, Soo Bin Choi, Bosung Ku, Dong Woo Lee, Sang-Yun Lee.
       INTRODUCTION: Central nervous system (CNS) drug development remains challenging because effective delivery across the blood-brain barrier (BBB) is difficult to predict preclinically. In vitro BBB models are increasingly used to evaluate barrier properties and drug transport, but platform variability and limited standardization hinder consistent interpretation and translational use.
    AREAS COVERED: This review summarizes major cell-based in vitro BBB models for CNS drug development, focusing on static, dynamic, microfluidic, induced pluripotent stem cell-derived, and three-dimensional (3D) BBB platforms. Emphasis is placed on model applicability for permeability assessment, transporter activity, exposure kinetics, spatial distribution, and translational prediction. Relevant literature was searched using PubMed, Web of Science, and Google Scholar up to 2025.
    EXPERT OPINION: Although in vitro BBB models have advanced substantially, no single system fully reproduces the complexity of the in vivo BBB. The major limitation is persistent inconsistency across models, which complicates interpretation and limits confidence in their translational application. Static models are practical but provide only partial representation of BBB function, whereas stem cell-based and microfluidic platforms offer greater physiological relevance but face reproducibility and scalability challenges. Future progress should prioritize context-of-use-driven model selection, tiered validation, and harmonized reporting to support reliable decision-making in CNS drug development.
    Keywords:  Blood-brain barrier; In vitro blood-brain barrier models; central nervous system drug delivery; new drug development; translational relevance
    DOI:  https://doi.org/10.1080/17425247.2026.2676068
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