bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–02–15
39 papers selected by
Luca Bolliger, lxBio
  1. When Barriers Break: Tight Junction Regulation and Dynamic Alterations of Barrier Integrity in Neurological Injury.
  2. Pharmacological modulation of the blood-brain barrier: Mechanisms, therapeutic strategies, and emerging technologies.
  3. Current and emerging therapeutic strategies for amyotrophic lateral sclerosis: from pharmacological approaches to gene and stem cell therapies.
  4. Smart alginate-based biomaterials for neurodegenerative disease therapy: Innovations in delivery, regeneration, and clinical translation.
  5. From Evasion to Collapse: The Kinetic Cascade of TDP-43 and the Failure of Proteostasis.
  6. P2X7 receptors as targets for neuroprotection.
  7. Insulin Signaling in Alzheimer's Disease: Association with Brain Insulin Resistance.
  8. Anti-Inflammatory Effects of Polyphenols in Brain Microvascular Endothelial Cells Stimulated with TNF-α.
  9. Single-atom nanozymes: a new platform for central nervous system disease research.
  10. NX210c Demonstrates Therapeutic Potential to Restore Blood-Brain Barrier in a QSP Model of Relapsing-Remitting Multiple Sclerosis.
  11. Photobiomodulation repairs the blood-spinal cord barrier in a mouse model of spinal cord injury.
  12. Gut Dysbiosis and Microbiota-Derived Metabolites in Neurodegenerative Diseases: Molecular and Biochemical Mechanisms Along the Gut-Brain Axis.
  13. Tailoring treatments: pharmacogenomics in the management of neurodegenerative diseases.
  14. Systemic immune-metabolic interactions in patients with amyotrophic lateral sclerosis: correlations of plasma cytokines with metabolic status.
  15. In Silico Prediction and Validation of the Permeability of Small Molecules Across the Blood-Brain Barrier.
  16. Gene-targeted versus broad-spectrum therapies in ALS: comparative lessons and strategic outlook.
  17. A systematic review and meta-analysis of the relationship between neuroinflammation and blood-brain barrier based on in vitro models.
  18. Eye tracking as a digital biomarker in neurodegenerative diseases.
  19. Research progress of blood-brain barrier penetrating and brain diseases therapy by natural biopolymer - based nanomedicine delivery systems.
  20. Oligodendrocyte: Development, Plasticity, Biological Functions, Diseases, and Therapeutic Targets.
  21. Endothelial miR-7052 Safeguards Blood-Brain Barrier Integrity During Endotoxemia by Co-repressing ANGPT2 and PDE5A.
  22. Transcriptomic profiling uncovers mis-splicing and gene fusions in amyotrophic lateral sclerosis.
  23. Sobetirome-Loaded Chitosan Nanoparticles for Controlled Release and Enhanced Blood-Brain Barrier Permeability in Neurodegenerative Disorders.
  24. From Dish to Trial: Building Translational Models of ALS.
  25. Big Tau: Structure, Evolutionary Divergence, and Emerging Roles in Cytoskeletal Dynamics and Tauopathies.
  26. Targeting metabolic dysfunction in amyotrophic lateral sclerosis: therapeutic potential of GLP-1 receptor agonists.
  27. Ultrasound-mediated blood-brain barrier opening for targeted neurological drug delivery.
  28. Superoxide dismutase impacts extracellular vesicle shedding and uptake.
  29. [Combination of amyotrophic lateral sclerosis with Alzheimer's disease].
  30. The Impact of Zinc on Cellular Dynamics, Brain Function, and its Therapeutic Potential in Neuronal Regeneration.
  31. A physics-informed neural network framework for quantitative analysis of transcytosis and physical diffusion in an in vitro BBB.
  32. The E-Value in Regression: A Useful, Simple, Easily Understood, and Easily Applied Statistic.
  33. New Insights on Mitochondria-Targeted Neurological Drugs.
  34. Immune crosstalk in Alzheimer's and Parkinson's disease: insights from Drosophila models into the brain-peripheral immune axis.
  35. Treating SOD1-ALS with tofersen results in nonprogressive chronic ALS-a case series from Iceland.
  36. The application of CRISPR-Cas9 system in brain diseases.
  37. Emerging role of gut microbiota extracellular vesicle in neurodegenerative disorders and insights on their therapeutic management.
  38. CRISPR-Cas technologies in neurodegenerative disorders: mechanistic insights, therapeutic potential, and translational challenges.
  39. Airborne particulates and brain health: The role of PM2.5 in blood-brain-barrier dysfunction.
  1. Cells. 2026 Jan 26. pii: 232. [Epub ahead of print]15(3):
    When Barriers Break: Tight Junction Regulation and Dynamic Alterations of Barrier Integrity in Neurological Injury.
    Kayli N Colpitts, James W Grau.
      The blood-brain barrier and blood-spinal cord barrier (BBB/BSCB) are essential protective components for the healthy functioning of the central nervous system (CNS). While these barriers protect the CNS from peripheral factors, such as immune cells and blood products, they can become disrupted in pathological conditions and injury. The neurovascular unit (NVU) is composed of endothelial cells (ECs), pericytes, astrocytes, microglia, and neurons, all of which contribute to proper function and the maintenance of the BBB/BSCB. Tight junctions (TJs) unite cellular components and are modulated by both intrinsic and extrinsic factors. Systemic processes, such as pain (nociceptive activity), inflammation, and blood hemostasis, can impact BBB/BSCB function, often leading to a disrupted barrier and increased peripheral infiltration. This, in turn, can increase neuroinflammation and drive microglia activation, progressive hemorrhagic necrosis (PHN), and matrix metalloproteinase (MMP) activity. Targeting these processes and mitigating the deleterious effects of BBB/BSCB breakdown represents a key therapeutic target after neural injury and other pathological conditions.
    Keywords:  barrier disruption; blood-brain barrier; blood-spinal cord barrier; neural injury; neuroinflammation; tight junction proteins; tight junctions
    DOI:  https://doi.org/10.3390/cells15030232
  2. Pharmacol Rev. 2026 Jan 16. pii: S0031-6997(26)00006-2. [Epub ahead of print]78(2): 100118
    Pharmacological modulation of the blood-brain barrier: Mechanisms, therapeutic strategies, and emerging technologies.
    Iosif Pediaditakis, Serena Tsakali, Maddie R Lemieux, Matthew Brennan, William H Robinson, Spyridon Papapetropoulos, Andreas Papapetropoulos.
      The blood-brain barrier (BBB) is a specialized vascular interface that safeguards central nervous system homeostasis by tightly regulating molecular exchange between blood and the brain. While essential for neuroprotection, its restrictive permeability limits therapeutic access, and its dysfunction is increasingly recognized as a driver of pathology across neurodegenerative, inflammatory, cerebrovascular, traumatic, and rare genetic disorders. In this review, we provide a comprehensive overview of pharmacological strategies to modulate BBB function, linking mechanistic insights into tight junction dynamics, transporter networks, endothelial-pericyte interactions, and immune crosstalk to emerging therapeutic approaches. We discuss interventions ranging from small molecules, peptides, and biologics to nanocarriers, noninvasive technologies, gene therapy, and stem cell-based strategies, highlighting their applications in 2 key translational contexts: transient enhancement of drug delivery and restoration of barrier integrity in disease. Ongoing challenges include ensuring safety, accounting for patient heterogeneity, and addressing the limitations of current experimental models. Finally, we consider how advances in BBB-on-chip systems, patient-specific induced pluripotent stem cell-derived models, and novel molecular targets are accelerating translation. Collectively, pharmacological modulation of the BBB, whether by reversible opening to enhance delivery or by reinforcing its protective function, represents a transformative frontier in central nervous system therapy. SIGNIFICANCE STATEMENT: The blood-brain barrier (BBB) is both a vital safeguard of neural homeostasis and a central obstacle to drug development in the central nervous system. This review integrates mechanistic insights into BBB regulation with translational advances in pharmacology and biotechnology, highlighting strategies that restore barrier integrity in disease and enhance therapeutic delivery. Emerging approaches, including gene therapy, nanotechnology, stem cell-based interventions, and next-generation human-relevant BBB models, illustrate how pharmacological innovation can overcome longstanding challenges and expand therapeutic access to the brain.
    DOI:  https://doi.org/10.1016/j.pharmr.2026.100118
  3. Front Neurol. 2026 ;17 1729302
    Current and emerging therapeutic strategies for amyotrophic lateral sclerosis: from pharmacological approaches to gene and stem cell therapies.
    Ze Wang, Jiajun Huang, Di Yun.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that involves upper and lower motor neurons, severely impairing patients' quality of life. The complex interaction of genetic and environmental factors in ALS pathophysiology complicates therapeutic development. Currently available disease-modifying pharmacological therapies for ALS offer limited efficacy, only slowing disease progression to a modest degree. The recent market withdrawal of a previously approved therapy (AMX0035) further underscores the challenges in this field. Biological targets for ALS and related neurodegenerative diseases offer a unique avenue for therapeutic intervention. With the advancement of genetic engineering technology, innovative therapies such as Stem cell therapy and gene therapy are also discussed, offering a promising horizon for ALS treatment. In addition, the management of ALS symptoms plays a key role in improving the daily lives of people with the disease. In this review, we summarize various strategies for treating ALS, providing an overview of the disease.
    Keywords:  amyotrophic lateral sclerosis (ALS); gene therapy; pharmacological treatments; potential therapeutic targets; stem cell therapy
    DOI:  https://doi.org/10.3389/fneur.2026.1729302
  4. Int J Biol Macromol. 2026 Feb 07. pii: S0141-8130(26)00614-8. [Epub ahead of print]348 150688
    Smart alginate-based biomaterials for neurodegenerative disease therapy: Innovations in delivery, regeneration, and clinical translation.
    Mostafa M El-Sheekh, Nada E Ramadan, Farah M Elshikh, Fatma R Youssef, Jehan W Salem, Mona T Sharaf, Slwan H Elmor, Sameh Samir Ali.
      Neurodegenerative diseases and central nervous system (CNS) injuries remain among the most challenging disorders to treat due to their complex pathophysiology, limited regenerative capacity, and the presence of the blood-brain barrier (BBB), which severely restricts therapeutic delivery. Despite extensive research efforts, most current interventions are palliative and fail to modify disease progression. Biomaterial-based strategies have emerged as promising adjuncts to conventional therapies, with alginate-based systems attracting increasing attention due to their biocompatibility, mild aqueous processing, and tunable physicochemical properties. This review critically examines the role of alginate-based biomaterials in CNS drug delivery, tissue engineering, and regenerative medicine, with particular emphasis on their ability to address key translational barriers, including BBB penetration, immune compatibility, and localized, sustained therapeutic release. We discuss how alginate can be engineered into nanoparticles, hydrogels, microspheres, and three-dimensional scaffolds to engage distinct transport mechanisms such as receptor-mediated transcytosis, adsorptive-mediated uptake, and nose-to-brain delivery while preserving the stability of labile bioactive cargos. Quantitative design parameters relevant to CNS applications, including stiffness ranges, degradation kinetics, and porosity, are highlighted to support rational material selection. Importantly, this review distinguishes between the structural and delivery functions of alginate as a carrier material and the biological effects mediated by encapsulated therapeutic agents, avoiding overstatement of alginate's intrinsic bioactivity. Disease-specific applications in Alzheimer's disease, Parkinson's disease, spinal cord injury, and brain tumors are discussed in a balanced manner, with clear differentiation between preclinical findings and clinically validated evidence. Current limitations related to mechanical robustness, batch-to-batch variability, and regulatory scalability are critically evaluated, alongside emerging solutions such as surface functionalization, hybrid biomaterials, and advanced fabrication strategies. Overall, this review provides a realistic and integrative framework for understanding the opportunities and constraints of alginate-based systems in CNS therapy, emphasizing that while alginate offers significant preclinical promise, substantial translational challenges remain before widespread clinical adoption can be achieved.
    Keywords:  Alginate-based biomaterials; Neurodegenerative disease therapy; Stimuli-responsive drug delivery
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150688
  5. Int J Mol Sci. 2026 Jan 23. pii: 1136. [Epub ahead of print]27(3):
    From Evasion to Collapse: The Kinetic Cascade of TDP-43 and the Failure of Proteostasis.
    Angelo Jamerlan, John Hulme.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases that, despite the availability of symptomatic and modestly beneficial treatments, still lack therapies capable of halting disease progression. A histopathological hallmark of both diseases is the cytoplasmic deposition of TDP-43 in neurons, which is attributed to both intrinsic (e.g., mutations, aberrant cleavage) and extrinsic factors (e.g., prolonged oxidative stress, impaired clearance pathways). Mutations and certain PTMs (e.g., cysteine oxidation) destabilize RNA binding, promoting monomer misfolding and increasing its half-life. Disruptions to core ubiquitin-proteasome system (UPS) subunits impede efficient processing, contributing to the clearance failure of misfolded TDP-43 monomers. The accumulation of monomers drives phase separation within stress granules, creating nucleation hotspots that eventually bypass the thermodynamic barrier, resulting in exponential growth. This rapid growth then culminates in the failure of the autophagy-lysosome pathway (ALP) to contain the aggregation, resulting in a self-sustaining feed-forward loop. Here, we organize these factors into a conceptual kinetic cascade that links TDP-43 misfolding, phase separation, and clearance failure. Therapeutic strategies must therefore move beyond simple clearance and focus on targeting these kinetic inflection points (e.g., oligomer seeding, PTM modulation).
    Keywords:  TDP-43 proteinopathy; amyotrophic lateral sclerosis (ALS); autophagy-lysosome pathway (ALP); frontotemporal dementia (FTD); neurodegeneration; phase separation; post-translational modifications (PTMs); proteostasis collapse; ubiquitin-proteasome system (UPS)
    DOI:  https://doi.org/10.3390/ijms27031136
  6. Neuropharmacology. 2026 Feb 09. pii: S0028-3908(26)00050-X. [Epub ahead of print]289 110877
    P2X7 receptors as targets for neuroprotection.
    Victoria Maneu, Antonio G García.
      In this review we explore the potential of P2X7 receptor blockers to elicit neuroprotection. This conjecture is based on a reasonably well-established role of this receptor in activating glial cells to maintain a chronic low-level neuroinflammatory state in the brain of patients suffering some neurodegenerative diseases (NDDs). In this context we briefly discuss evidence supporting the role of P2X7 receptors (P2X7) in the pathogenesis of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. From a pathogenic point of view these diseases have specific features but all share a low level neuroinflammatory state with microglia activation and enhanced P2X7 expression. Next, we comment on available P2X7 blockers with central nervous system (CNS) target engagement. Then, we deal with the proof-of-concept concerning the potential of some blockers to mitigate the neuroinflammatory state in preclinical models of the target diseases above mentioned. We follow with a discussion of the scarce number of clinical trials done with some P2X7 blockers in inflammatory diseases. Finally, we discuss the current discrepancy between promising preclinical data and the limited number of clinical trials exploring P2X7 antagonists in NDDs. We provide some clues that may boost clinical trials with single P2X7 blockers but particularly, with their association with other medicines currently being used or that are intended to be prescribed in the treatment of NDDs.
    Keywords:  Neurodegeneration; Neuroinflammation; Neuroprotection; P2X7 ligands; P2X7 receptors
    DOI:  https://doi.org/10.1016/j.neuropharm.2026.110877
  7. Int J Mol Sci. 2026 Jan 26. pii: 1222. [Epub ahead of print]27(3):
    Insulin Signaling in Alzheimer's Disease: Association with Brain Insulin Resistance.
    Monika Pliszka, Leszek Szablewski.
      Insulin is an anabolic hormone involved in the regulation of several processes, such as the storage of glucose into glycogen, decrease of glucose output, stimulation of glucose transport into cells, etc. The hormone binds to its receptor, thereby activating an intracellular signaling cascade. Once activated, the insulin receptor (INSR) phosphorylates multiple intracellular substrates, which initiate the downstream signaling pathway. The nature of insulin signaling pathways may vary depending on the organ or tissue. In the central nervous system (CNS), INSRs are expressed in all cell types. This observation may suggest that insulin signaling is involved in important and diverse processes. It regulates glucose metabolism, supports cognitive functions, enhances the outgrowth of neurons, as well as plays a role in the modulation of release and uptake of catecholamine, among other roles. Importantly, insulin can freely cross the blood-brain barrier (BBB) from the circulation and is also synthesized locally within the brain. Insulin resistance (IR) impairs insulin signaling, which may accelerate brain aging, affect plasticity, and potentially contribute to neurodegeneration. Dysregulation of insulin signaling has been implicated in several diseases, including diabetes mellitus, metabolic syndrome, certain cancers, and neurodegenerative diseases, such as Alzheimer's disease. There are two principal insulin signaling pathways: the PI3K/AKT pathway, primarily associated with metabolic effects, and the MAPK pathway, which is involved in cell growth, survival, and gene expression. Our review describes the role of insulin in the human brain, as well as the disturbances in insulin signaling resulting from brain insulin resistance, with a particular focus on its association with Alzheimer's disease.
    Keywords:  Alzheimer’s disease; MAPK signaling pathway; PI3K/AKT signaling pathway; insulin resistance; insulin signaling pathways
    DOI:  https://doi.org/10.3390/ijms27031222
  8. Int J Mol Sci. 2026 Jan 28. pii: 1316. [Epub ahead of print]27(3):
    Anti-Inflammatory Effects of Polyphenols in Brain Microvascular Endothelial Cells Stimulated with TNF-α.
    Joanna Czpakowska, Andrzej Glabinski, Piotr Szpakowski.
      The blood-brain barrier (BBB) is a structure that regulates the exchange of substances between the peripheral circulation and the central nervous system (CNS), thereby protecting this environment. An increase in BBB permeability may lead to the influx of inflammatory cells, resulting in neuroinflammation and neurodegeneration. The integrity of the BBB is maintained due to the specific properties of brain endothelial cells. Considering the importance of brain endothelial cells in the BBB during inflammatory processes, these cells may be a target for anti-inflammatory agents. Polyphenols are substances exhibiting the ability to decrease inflammation; therefore, in our research, we aimed to examine their effectiveness in a brain endothelial cell culture stimulated with the pro-inflammatory cytokine TNF-α. The tested polyphenols were myricetin, chrysin, resveratrol, and curcumin. ELISA tests revealed that myricetin and chrysin decreased the concentrations of the pro-inflammatory cytokines IL-1ß, IL-6, and IL-8 secreted by brain endothelial cells. The results of flow cytometry indicate that chrysin and resveratrol are the most potent in downregulating the expression of VCAM-1 on the surface of brain endothelial cells. The obtained results confirm the anti-inflammatory potential of polyphenols in brain endothelial cells. The selected polyphenols also contribute to increasing brain endothelial cell viability and act as antioxidants.
    Keywords:  blood–brain barrier; brain endothelial cells; chrysin; curcumin; inflammation; myricetin; neurodegeneration; neuroinflammation; polyphenols; resveratrol
    DOI:  https://doi.org/10.3390/ijms27031316
  9. Chem Commun (Camb). 2026 Feb 10.
    Single-atom nanozymes: a new platform for central nervous system disease research.
    Yue Yang, Ya-Qi Zhu, Su-Yun Zhang, Meng-Zhu Zhou, Hao Sun, Xiao-Ling Zhang, Xuan Yi, Ming-Xuan Liu.
      Featuring complex neural architectures, the central nervous system (CNS) poses a high risk of irreversible damage or chronic diseases upon injury by inflammatory factors. However, due to the existence of the blood-brain barrier (BBB), drugs can hardly penetrate the nervous system, making new therapeutic approaches urgently needed. Recently, single-atom nanozymes (SAzymes) have emerged as a promising platform for a wide range of therapeutic applications, capitalizing on their distinctive features including atomic-level dispersion of active sites, complete atom utilization, and a tunable coordination environment. Compared with traditional nanozymes, SAzymes exhibit superior catalytic activity, more decipherable structure-activity relationships, and greater tunability of their active site properties. Therefore, this review systematically summarizes and provides an in-depth discussion of typical single-atom nanozymes, including carbon materials, metal-organic frameworks (MOFs), metal oxides, and metal sulfides. Leveraging the anti-inflammatory and antibacterial properties, the roles of various SAzymes in brain injury, stroke, neurodegenerative diseases, biological monitoring, and neuroprotection have also been elaborated in recent years. Simultaneously, based on the latest developments in SAzyme research, novel therapeutic strategies for these diseases are further proposed. Finally, we conduct an in-depth analysis of the key challenges and future research directions for SAzymes.
    DOI:  https://doi.org/10.1039/d6cc00053c
  10. Int J Mol Sci. 2026 Jan 29. pii: 1349. [Epub ahead of print]27(3):
    NX210c Demonstrates Therapeutic Potential to Restore Blood-Brain Barrier in a QSP Model of Relapsing-Remitting Multiple Sclerosis.
    Giulia Russo, Fianne Sips, Simona Catozzi, Pauline Bambury, Annette Janus, Mario Torchia, Valentina Di Salvatore, Luca Emili, Daniel Röshammar, Francesco Pappalardo, Yann Godfrin.
      Blood-brain barrier (BBB) breakdown is a hallmark of several neurological disorders, including multiple sclerosis (MS). NX210c, a novel therapeutic peptide, has shown promise in restoring BBB integrity, in both preclinical and clinical settings, offering potential for use in MS populations and across various central nervous system conditions with overlapping mechanisms. In this study, we evaluated the therapeutic potential of NX210c in patients with relapsing-remitting MS (RRMS) using a previous quantitative systems pharmacology (QSP) model currently redesigned to capture the dynamic interplay between BBB integrity and immune system activity. We validated the QSP model using both preclinical and clinical datasets, and generated virtual populations representing healthy individuals and RRMS patients for in silico testing. NX210c was assessed as both a monotherapy and in combination with established MS treatments. Simulations predicted time course changes in key BBB integrity markers, including tight junction protein (TJP) expression and transendothelial electrical resistance (TEER), under various dosing regimens. NX210c treatment was associated with a significant attenuation of BBB degradation compared to untreated controls (~7-8% higher TJP expression and BBB electrical resistance). Furthermore, we investigated the long-term impact of NX210c on clinical outcomes such as relapse rates. Both 5 and 10 mg/kg doses (single cycle [thrice-weekly for 4 weeks]) induced improvement in disease activity in RRMS patients, as well as a 10 mg/kg dose (single or repeated 4-week cycles every 6 months) in highly active patients. Particularly when administered alongside one of five commonly used MS therapies (interferon β-1a, teriflunomide, cladribine, natalizumab, ocrelizumab), in the highly active subpopulation, the model on average predicted a reduction in relapse frequency in the 10 mg NX210c-treated group versus untreated group from four to no relapses over two years. These findings suggest that NX210c may enhance therapeutic efficacy in RRMS by promoting BBB restoration and modulating immune responses, offering a promising avenue for combination treatment strategies.
    Keywords:  NX210c; SCO-spondin; blood–brain barrier; neurodegenerative diseases; neuroinflammation; quantitative systems pharmacology; relapsing–remitting multiple sclerosis; tight junction proteins
    DOI:  https://doi.org/10.3390/ijms27031349
  11. Neural Regen Res. 2026 Jun 01. 21(6): 2475-2484
    Photobiomodulation repairs the blood-spinal cord barrier in a mouse model of spinal cord injury.
    Yangguang Ma, Yi Liu, Dongsheng Pan, Jiawei Zhang, Zhuowen Liang, Yi Wang, Xueyu Hu, Zhe Wang, Tan Ding.
      JOURNAL/nrgr/04.03/01300535-202606000-00062/figure1/v/2026-02-11T151048Z/r/image-tiff The blood-spinal cord barrier is crucial for preserving homeostasis of the central nervous system. After spinal cord injury, autophagic flux within endothelial cells is disrupted, compromising the integrity of the blood-spinal cord barrier. This disruption facilitates extensive infiltration of inflammatory cells, resulting in exacerbated neuroinflammatory responses, neuronal death, and impaired neuronal regeneration. Previous research has demonstrated that photobiomodulation promotes the regeneration of damaged nerves following spinal cord injury by inhibiting the recruitment of inflammatory cells to the injured site and restoring neuronal mitochondrial function. However, the precise mechanisms by which photobiomodulation regulates neuroinflammation remain incompletely elucidated. In this study, we established a mouse model of spinal cord injury and assessed the effects of photobiomodulation treatment. Photobiomodulation effectively cleared damaged mitochondria from endothelial cells in mice, promoting recovery of hindlimb motor function. Using microvascular endothelial bEnd.3 cells subjected to oxygen-glucose deprivation, we found that the effects of photobiomodulation were mediated through activation of the PINK1/Parkin pathway. Additionally, photobiomodulation reduced mitochondrial oxidative stress levels and increased the expression of tight junction proteins within the blood-spinal cord barrier. Our findings suggest that photobiomodulation activates mitochondrial autophagy in endothelial cells through the PINK1/Parkin pathway, thereby promoting repair of the blood-spinal cord barrier following spinal cord injury.
    Keywords:  PTEN-induced kinase 1; autophagy; blood–spinal cord barrier; endothelial cell; mitochondria; neuroinflammatory; photobiomodulation; repair; spinal cord injury; tight junction
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01098
  12. Molecules. 2026 Jan 30. pii: 490. [Epub ahead of print]31(3):
    Gut Dysbiosis and Microbiota-Derived Metabolites in Neurodegenerative Diseases: Molecular and Biochemical Mechanisms Along the Gut-Brain Axis.
    Patrycja Victoria Czaj, Karolina Szewczyk-Golec, Jarosław Nuszkiewicz, Alina Woźniak.
      Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) share key molecular features, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and progressive neuronal loss. Increasing evidence indicates that gut dysbiosis and alterations in microbiota-derived metabolites are involved in these processes through multiple pathways along the gut-brain axis. However, while broad compositional changes are well-documented, a critical knowledge gap remains regarding the specific biochemical signal transduction pathways translating dysbiosis into pathology. This narrative review addresses this gap by synthesizing current human and experimental studies addressing gut microbiota alterations in AD, PD, and ALS, with particular emphasis on the biochemical and molecular mechanisms mediated by gut-derived metabolites. Dysbiosis in neurodegenerative diseases is frequently associated with reduced abundance of short-chain fatty acid (SCFA)-producing bacteria and altered metabolism of SCFAs, bile acids, tryptophan-derived indoles, trimethylamine-N-oxide (TMAO), and lipopolysaccharides (LPS). These microbial metabolites have been shown to modulate intestinal and blood-brain barrier integrity, influence Toll-like receptor- and G protein-coupled receptor-dependent signaling, regulate microglial activation, and affect molecular pathways related to protein aggregation in experimental models. In addition, emerging evidence highlights the involvement of oxidative and nitrosative stress, immune-metabolic crosstalk, and altered xenobiotic metabolism in microbiota-host interactions during neurodegeneration. By integrating microbiological, metabolic, and molecular perspectives, this review underscores the important and emerging role of microbiota-derived molecules in neurodegenerative disorders and outlines key chemical and metabolic pathways that may represent targets for future mechanistic studies and therapeutic strategies.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; gut microbiota; gut–brain axis; microbiota-derived metabolites; neurodegeneration; oxidative stress; short-chain fatty acids
    DOI:  https://doi.org/10.3390/molecules31030490
  13. Acta Neurol Belg. 2026 Feb 10.
    Tailoring treatments: pharmacogenomics in the management of neurodegenerative diseases.
    Kishor Kumar Roy, Rashmi Kumari, Abhay Kumar Upadhyay, Satyajit Mohanty.
      Neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis are growing more common worldwide, yet treatment is still poor. Conventional therapies can have unforeseen side effects, produce poor medication reactions, and take longer to work. This persistent treatment gap highlights the need for novel approaches to these disorders' complex distinctions. Pharmacogenomics, which examines how genetic differences affect drug response, is a promising new subject and an urgent solution. Pharmacogenomics tailors medicine selection and administration to each patient's genetic profile, addressing the main causes of poor treatment response and preventable side effects. This research has enabled precision medicine that can improve neurodegenerative disease therapy and reduce harm. In this in-depth research, we examine neurodegenerative disease management issues, pharmacogenomics breakthroughs, and how incorporating genetics to clinical practice can improve outcomes. We examine the latest evidence that genetics affect drug breakdown, efficacy, and toxicity. We also discuss the challenges and opportunities of applying this knowledge. Pharmacogenomic approaches must be widely applied to make medicines for these awful disorders safer, more effective, and really suited to patient needs, according to our compilation.
    Keywords:  Alzheimer's disease; Amyotrophic lateral sclerosis; Genetic variability; Huntington's disease; Neurodegenerative disease; Parkinson's disease; Personalized medicine; Pharmacogenomics
    DOI:  https://doi.org/10.1007/s13760-025-02919-4
  14. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Feb 14. 1-11
    Systemic immune-metabolic interactions in patients with amyotrophic lateral sclerosis: correlations of plasma cytokines with metabolic status.
    Stephanie L Howe, Cory J Holdom, Pamela A McCombe, Robert D Henderson, Frederik J Steyn, Shyuan T Ngo.
       OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disease influenced by multiple biological processes. Altered energy metabolism, particularly hypermetabolism, is observed in some people living with ALS (plwALS) and is associated with faster progression. The mechanisms underlying this metabolic phenotype remain unclear. Inflammation has been proposed as a contributing factor. We examined whether plasma cytokines, as markers of systemic inflammation, are associated with energy expenditure in plwALS.
    METHODS: Plasma samples from 77 plwALS and 90 non-neurodegenerative controls were analyzed using a multiplex immunoassay quantifying 14 cytokines. Cytokine concentrations were compared between groups and examined in relation to body composition, resting energy expenditure, and functional capacity as inferred by the ALSFRS-R.
    RESULTS: Interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) concentrations were higher in plwALS than in controls prior to correction for multiple comparisons (p = 0.006; p.adj = 0.083, and p = 0.035; p.adj = 0.237, respectively). Hypermetabolism was more prevalent in the ALS cohort (36% compared to 11.5%, p < 0.001); however, cytokine concentrations were not significantly different across metabolic subgroups and showed no statistically significant association with metabolic index, energy expenditure, or functional measures.
    CONCLUSIONS: Findings confirm modest elevations in plasma levels of IL-6 and MCP-1 in ALS but provide no evidence that circulating cytokines correlate with hypermetabolism. Further studies integrating longitudinal and tissue-specific analyses are needed to clarify immune-metabolic mechanisms contributing to disease heterogeneity in ALS.
    Keywords:  Amyotrophic lateral sclerosis; cytokine; hypermetabolism; inflammation
    DOI:  https://doi.org/10.1080/21678421.2026.2627902
  15. Int J Mol Sci. 2026 Jan 31. pii: 1427. [Epub ahead of print]27(3):
    In Silico Prediction and Validation of the Permeability of Small Molecules Across the Blood-Brain Barrier.
    Favour Ajao, Dominique de Jong-Hoogland, Jakob P Ulmschneider, Martin B Ulmschneider, Edward Lambden.
      Understanding and predicting the ability of small-molecule drugs to cross the blood-brain barrier (BBB) is essential for developing treatments for neurodegenerative disorders such as Alzheimer's disease. In this study, we aim to computationally estimate BBB permeability for pharmacologically relevant molecules using an all-atom, unbiased molecular dynamics (MD) framework accelerated by elevated-temperature simulations. Our approach infers physiological permeabilities via elevated temperature passive diffusion trajectories, enabling quantitative ranking across a chemically diverse compound set. The computed permeabilities are compared with available in vitro and in silico data for control molecules. We further explore the molecular mechanisms underlying permeability differences through their free energy profiles and lipid contact analyses, revealing molecule-specific interactions with individual lipid species in the BBB membrane. This work introduces a novel combination of elevated-temperature MD and mechanistic decomposition to assess BBB permeability and applies it to candidate molecules with therapeutic potential in neurodegeneration.
    Keywords:  Alzheimer’s disease; blood–brain barrier; drug discovery; membrane permeability; molecular dynamics
    DOI:  https://doi.org/10.3390/ijms27031427
  16. J Genet Genomics. 2026 Feb 05. pii: S1673-8527(26)00042-1. [Epub ahead of print]
    Gene-targeted versus broad-spectrum therapies in ALS: comparative lessons and strategic outlook.
    Yihan Shen, Siyu Shen, Zhen-Ge Luo.
      Amyotrophic lateral sclerosis (ALS) is a relentless and fatal neurodegenerative disorder characterized by the progressive loss of motor neurons, leading to muscle weakness, paralysis, and ultimately, respiratory failure. Despite a growing understanding of its complex pathophysiology, therapeutic options remain limited. This review critically analyzes recent clinical advances by comparing two divergent strategies, including precision gene-targeted therapies for monogenic ALS subtypes and broad-spectrum agents for the wider sporadic population. While gene therapies like tofersen demonstrate clear molecular target engagement, their translation to robust clinical benefit remains a challenge. In contrast, broad-spectrum agents have faced consistent late-stage failures, often due to the disease's underlying diversity, which undermines a one-size-fits-all approach. We argue that this heterogeneity, coupled with a lack of predictive biomarkers and the difficulty of late-stage intervention, represents the core barrier to progress. The future of ALS therapeutics therefore depends on a strategic pivot toward personalized medicine. This requires prospectively stratifying patients, developing rational combination therapies, and intervening earlier in the disease course, ultimately treating ALS as a syndrome of distinct molecular diseases rather than a single entity.
    Keywords:  Amyotrophic lateral sclerosis; Clinical trials; Neurodegeneration; Precision medicine; Rare disease
    DOI:  https://doi.org/10.1016/j.jgg.2026.01.012
  17. Biochem Biophys Rep. 2026 Mar;45 102479
    A systematic review and meta-analysis of the relationship between neuroinflammation and blood-brain barrier based on in vitro models.
    Junwei Zhao, Anyongqi Wang, Xiang Li.
      The blood-brain barrier (BBB) plays a crucial role in maintaining homeostasis within the central nervous system (CNS). Neuroinflammation disrupts the integrity of the BBB. However, there is a lack of comprehensive synthesis of in vitro evidence on this topic. This study aims to systematically review in vitro research examining the effects of neuroinflammatory stimuli on the structure and function of the BBB. PubMed, EMBASE, and Web of Science were searched for studies published between November 2014 and November 2024. Included studies employed in vitro BBB models to assess effects of defined neuroinflammatory on structural and functional. Pooled standardized mean differences (SMD) with 95 % confidence intervals (CI) were calculated using random effects models. Meta-analysis was performed using R. Overall, 55 studies were included. Neuroinflammation was found to significantly decrease transendothelial electrical resistance (TEER) (-2.15, 95 % CI [-2.73, -1.56]) while increasing permeability (2.75, 95 % CI [1.71, 3.79]). Subgroup analyses showed that co-culture models exhibited more severe disruptions compared to mono-cultures measured by a significant decrease in TEER (p < 0.05). Human-derived cells displayed heightened decreases in TEER and increased permeability compared to non-human derived cells (p < 0.05). Co-cultures of endothelial cells and pericytes exhibited pronounced effects of decreased TEER compared to endothelial cells alone (p < 0.05). Stimulation periods exceeding 24 h led to significant changes. Lipopolysaccharide (LPS) caused significant disruptions. Experiments conducted with transwell systems were more sensitive to changes in TEER compared to non-transwell systems (p < 0.05). In vitro evidence confirms neuroinflammation disrupts BBB integrity through reduced TEER, increased permeability. Human-derived cells, particularly hiPSC-derived models, endothelial-pericytes co-cultures, and exposure to LPS exceeding 24 h most effectively replicate pathophysiological disruption, potentially offering optimal platforms for exploring neurological disease-related mechanisms and therapeutic strategy in the future.
    Keywords:  Blood-brain barrier (BBB); In vitro models; Meta-analysis; Neuroinflammatory; Permeability; Transendothelial electrical resistance (TEER)
    DOI:  https://doi.org/10.1016/j.bbrep.2026.102479
  18. J Neurol. 2026 Feb 10. 273(2): 133
    Eye tracking as a digital biomarker in neurodegenerative diseases.
    Paul S Giacomini, Patrice Voss, Virginia Devonshire, Raphael Schneider, Gabrielle Macaron, Shamiza Hussein, François Blanchette, Étienne de Villers-Sidani.
      Oculomotor abnormalities are a common finding in neurodegenerative diseases due to degeneration of neural pathways and brain regions involved in controlling eye movements. Pathological changes to the dorsolateral prefrontal cortex, basal ganglia, superior colliculus and cerebellum produce subtle changes in eye-movement metrics that may not be detected by clinical examination. The present review addresses the potential use of eye-movement biomarkers in neurodegenerative conditions such as multiple sclerosis, Parkinson's disease, Alzheimer's disease and other dementias, and amyotrophic lateral sclerosis. Eye-movement metrics such as saccades, anti-saccades, fixation and smooth pursuit are prognostic of disease progression, can differentiate pathologic subtypes as an aid to diagnosis, and enable clinicians to evaluate early worsening of motor and cognitive function. The cost of medical technologies limits their optimal use and accessibility in clinical practice. The shortage of subspecialist neurologists further limits access to care. New eye-tracking technologies incorporated into widely-accessible digital devices such as smart phones and tablets now permit detailed assessments with minimal equipment requirements, providing an important non-invasive and potentially cost-effective method for patient evaluation in routine clinical practice and as an aid to treatment decision-making. Digital biomarkers can be readily employed by healthcare professionals such as family physicians, nurses and pharmacists to bridge the care gaps, potentially providing them with powerful tools that can be broadly adopted to improve the delivery of care to patients with neurodegenerative conditions.
    Keywords:  Alzheimer’s disease; Digital biomarkers; Eye movements; Multiple sclerosis; Neurodegenerative diseases; Oculomotor; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s00415-026-13666-8
  19. Mater Today Bio. 2026 Apr;37 102849
    Research progress of blood-brain barrier penetrating and brain diseases therapy by natural biopolymer - based nanomedicine delivery systems.
    Lijing Qin, Xiu Wang, Tongjuan Liang, Yongyi Bi, Zhijun Guo, Wenzhong Li, Wanjun Liang.
      Brain diseases are one of the most critical threats to human health. The blood-brain barrier (BBB) prevents drugs from entering the brain, rendering standard treatments for neurological illnesses ineffective. In recent years, there has been an increase in interest in nanotechnology-based research to develop innovative drug delivery systems (NDDS) for drug loading, BBB penetration, and precision delivery to diseased areas. Nanocarriers made from natural biomaterials, in particular, solve the drawbacks of standard nanocarriers, such as low stability and inadequate targeting, while simultaneously providing benefits such as simplicity of modification and good biodegradability. This review focuses on the most recent advances in NDDS based on natural biomaterials for overcoming the BBB in treating brain diseases, with a particular emphasis on the methods and mechanisms by which natural biopolymers-such as polysaccharides, peptides, and polynucleotides-break through the BBB and enhance brain-targeted delivery. We explore current challenges and future application prospects of natural biopolymers in permeable nanomedicine delivery systems for the BBB, aiming to provide key insights for advancing cross-BBB delivery platforms toward smarter, multifunctional development, subsequent research, and translational applications.
    Keywords:  Biopolymers; Blood-brain barrier penetrating; Brain diseases therapy; Nano drug delivery systems; Natural biological materials
    DOI:  https://doi.org/10.1016/j.mtbio.2026.102849
  20. MedComm (2020). 2026 Feb;7(2): e70618
    Oligodendrocyte: Development, Plasticity, Biological Functions, Diseases, and Therapeutic Targets.
    Qiong Xiang, Ruo-Lan Shi, You-Xia Huang, Li-Ni Liu, Jia-Sheng Tao, Xian-Hui Li, Xiao-Da Li.
      In the past few years, the incidence rate of central nervous system (CNS) diseases is still growing. Meanwhile, the molecular mechanism on the pathogenesis of neurological diseases remains elusive. Oligodendrocyte progenitor cells (OPCs) are distributed in the whole CNS and represent a population of migrating and proliferating adult progenitor oligodendrocytes that can be differentiated into oligodendrocytes (OLs). The main function of OLs is to produce myelin, the membrane wrapping tightly around the axon, which are associated with the myelination and remyelination. During regeneration, the new OLs from OPCs can regenerate lost myelin, which prevents axonal degeneration and restores its plasticity and function. Considering these energy-consuming processes, the high metabolic turnover OLs are susceptible to neurotoxic factors and its excitatory toxicity. Thus, the pathogenesis of OPC and OL are proven in neurological diseases, such as multiple sclerosis, Alzheimer's disease, major psychiatric diseases, and epilepsy. The current study reviewed the development, plasticity as well as application of OPCs and OLs researches on CNS diseases. Additionally, the effective methods and bioengineering technologies as well as biomaterials relevant to regenerative medicine are also discussed, which could provide the novel insight into the therapeutic treatment of those diseases, exploring new pathological clues, identifying the key molecules and targets as well as the potential biomarkers.
    Keywords:  axonal plasticity; bioengineering technologies; central nervous system diseases; oligodendrocyte progenitor cells; oligodendrocytes
    DOI:  https://doi.org/10.1002/mco2.70618
  21. Mol Neurobiol. 2026 Feb 12. 63(1): 437
    Endothelial miR-7052 Safeguards Blood-Brain Barrier Integrity During Endotoxemia by Co-repressing ANGPT2 and PDE5A.
    Wenyuan Yang, Haigang Wu.
      Sepsis-associated inflammation compromises the blood-brain barrier (BBB), yet the endothelial microRNA circuitry that buffers barrier failure remains poorly defined. Here we identify endothelial miR-7052 as a stress-suppressed regulator of BBB integrity. In human and murine brain microvascular endothelium, lipopolysaccharide (LPS) reduces mature miR-7052 via a VEGFR2-JNK signaling arm. Loss of miR-7052 de-represses ANGPT2 and PDE5A, attenuates Tie2 signaling, and perturbs cGMP homeostasis, yielding disrupted junctional continuity, reduced transendothelial electrical resistance (TEER), and increased macromolecular flux. Restoring miR-7052 increases TEER, lowers 4- and 70-kDa tracer permeability, and preserves ZO-1/claudin-5 organization. Mechanistically, dual-luciferase reporters confirm direct repression of ANGPT2 and PDE5A; prime-editing of endogenous 3'UTR seed sites abolishes miR-7052 control and eliminates miR-dependent changes in transcript half-life. Epistasis tests position both targets downstream: recombinant ANGPT2 partially reverses miR-7052-mediated protection, whereas pharmacological PDE5 inhibition phenocopies barrier stabilization. In vivo, endothelial-specific AAV9 delivery of miR-7052 limits LPS-evoked BBB leakage and reduces microvessel ANGPT2 with concordant reinforcement of BBB transcripts. Together, these data establish miR-7052 as a nodal controller coupling inflammatory receptor input to multi-target suppression of permeability drivers, nominating miR-7052 replacement and combinatorial targeting of the ANGPT2/Tie2 and PDE5A/cGMP axes as therapeutic strategies to preserve the BBB in sepsis.
    Keywords:  Angiopoietin-2 (ANGPT2); C-Jun N-terminal kinase (JNK); Endothelial dysfunction; MiR-7052; Phosphodiesterase 5A (PDE5A); Sepsis; Vascular endothelial growth factor (VEGF)
    DOI:  https://doi.org/10.1007/s12035-026-05716-z
  22. medRxiv. 2026 Feb 06. pii: 2026.02.05.26345503. [Epub ahead of print]
    Transcriptomic profiling uncovers mis-splicing and gene fusions in amyotrophic lateral sclerosis.
    NYGC ALS Consortium
      Advances in transcriptomics have transformed our understanding of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, revealing disrupted gene expression profiles and highlighting the multi-system biology of ALS. Despite major advances, transcriptomic studies have only begun to capture the complexity and the molecular hierarchy of transcriptomic alterations in ALS. To resolve and characterize the transcriptome in ALS, we performed a comprehensive reanalysis of bulk RNA sequencing from the New York Genome Center ALS Consortium cohort across five post-mortem tissues including motor and frontal cortex, cervical and lumbar spinal cord, and cerebellum. By deploying dual analytical pipelines - one reference-based to model canonical events and one de novo to detect transcript structural novelties - we disentangled the quantitative and qualitative architectures of ALS. Our reference-based analysis revealed that ALS transcriptome is defined primarily by splicing failure rather than changes in gene expression. Aberrant splicing events, particularly intron retention, outnumbered differentially expressed genes by an order of magnitude. This widespread loss of fidelity disproportionately affected RNA-binding proteins, suggesting a collapse in their autoregulatory feedback loops. Deconvolution of these signals identified distinct cellular vulnerabilities: transcriptional disruptions were enriched in glial cells in sporadic cases but in neuronal cells in C9ORF72-positive cases. Furthermore, we observed sex-specific dysregulation, with male patients exhibiting greater disruption in guanosine triphosphatase signaling and ciliary organization pathways. In parallel, our de novo analysis uncovered a significant burden of disease-specific gene fusions that were absent in controls. Whole-genome sequencing of the same individuals, together with a larger reference population confirmed that disease-specific fusions do not arise from genomic structural variants, indicating a transcriptional rather than genomic origin. Investigation into the mechanism of these RNA-based fusions revealed a critical deviation in splice site definition: while canonical splice junctions exhibit a high density of binding motifs for polyA-binding or 3'-cleaveage proteins approximately 50 base pairs upstream of the splice donor site (left junction), ALS-specific fusion junctions displayed a dramatic depletion of these motifs in the same region. Functionally, the presence of these sparse disease-specific fusions was strongly correlated with severe splicing outliers in genes governing guanosine triphosphatase activity, converging with the tissue- and male-specific defects identified in our reference-based analysis. Altogether, our results delineated a transcriptome characterized by aberrant splicing with tissue-and sex-specific changes and identified structural-variant-independent RNA fusions as candidate disease modifiers that may amplify pathology. This integrated view provides a mechanistic scaffold for splicing-centered and RNA-structural therapeutic strategies for ALS.
    DOI:  https://doi.org/10.64898/2026.02.05.26345503
  23. Macromol Biosci. 2026 Feb;26(2): e00629
    Sobetirome-Loaded Chitosan Nanoparticles for Controlled Release and Enhanced Blood-Brain Barrier Permeability in Neurodegenerative Disorders.
    Buse Penceci, Cem Bülent Ustundag, Rabia Cakir.
      Neurodegenerative diseases represent a major global health challenge due to their progressive nature and lack of curative therapies. Developing innovative strategies to protect and regenerate neuronal structures is therefore crucial. In recent years, Sobetirome, a synthetic thyromimetic compound, has emerged as a promising therapeutic candidate for neurodegenerative disorders owing to its neuroprotective and regenerative potential. However, its clinical efficacy is limited by the poor permeability of the blood-brain barrier. Enhancing brain delivery through controlled transport systems could therefore improve therapeutic outcomes. In this study, Sobetirome was encapsulated into chitosan-based nanoparticles to enhance its stability, bioavailability, and blood-brain barrier penetration. An in vitro neurodegeneration model was established using SH-SY5Y cells treated with lysophosphatidylcholine, and a Caco-2 cell line was used to evaluate blood-brain barrier permeability. The nanoparticles showed an average size of 137.7 nm, a low polydispersity index (0.1), and a zeta potential of +21 mV, indicating stability and uniformity. FTIR analysis confirmed successful drug encapsulation, while encapsulation and loading efficiencies reached 91.2% and 65.15%, respectively. In vitro release studies demonstrated a controlled release profile, with 73.39% of Sobetirome released after 32 h. Cellular assays revealed that Sobetirome-loaded nanoparticles enhanced SH-SY5Y cell viability, proliferation, neuroprotection, and regenerative effects compared to free Sobetirome. Lower nanoparticle concentrations reduced apoptosis and improved cellular uptake. SEM imaging confirmed spherical morphology and nanoscale dimensions, consistent with DLS measurements. Overall, these results suggest that Sobetirome-loaded chitosan nanoparticles are a promising platform for neurodegenerative disease therapy, providing improved bioavailability, controlled drug release, and potential for systemic delivery to optimize therapeutic outcomes.
    Keywords:  BBB; chitosan nanoparticles; neurodegenerative disorders; sobetirome
    DOI:  https://doi.org/10.1002/mabi.202500629
  24. Cells. 2026 Jan 27. pii: 247. [Epub ahead of print]15(3):
    From Dish to Trial: Building Translational Models of ALS.
    Ilias Salamotas, Sotiria Stavropoulou De Lorenzo, Aggeliki Stachtiari, Apostolos Taxiarchis, Magda Tsolaki, Iliana Michailidou, Elisavet Preza.
      Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, marked by progressive degeneration of upper and lower motor neurons. Clinically, genetically, and pathologically heterogeneous, ALS poses a major challenge for disease modeling and therapeutic translation. Over the past two decades, induced pluripotent stem cells (iPSCs) have reshaped our understanding of ALS pathogenesis and emerged as a promising translational platform for therapy development. ALS modeling has further expanded with the advent of three-dimensional systems, including ALS-on-chip platforms and organoid models, which better capture cell-cell interactions and tissue-level phenotypes. Despite these advances, effective disease-modifying therapies remain elusive. Recent clinical trial setbacks highlight the need for improved trial design alongside robust, translational iPSC models that can better predict therapeutic response. Nonetheless, the outlook is promising as large iPSC patient cohorts, quantitative phenotyping combined with genetically informed patient stratification, and reverse translational research are beginning to close the gap between in vitro discovery and clinical testing. In this review, we summarize the major advances in iPSC technology and highlight key iPSC-based studies of sporadic ALS. We further discuss emerging examples of iPSC-informed therapeutic strategies and outline the challenges associated with translating iPSC-derived mechanistic insights and pharmacological findings into successful clinical therapies.
    Keywords:  NMJ; clinical trials; iPSC; organoids; preclinical models; sporadic ALS; therapeutic strategies
    DOI:  https://doi.org/10.3390/cells15030247
  25. Cells. 2026 Jan 27. pii: 241. [Epub ahead of print]15(3):
    Big Tau: Structure, Evolutionary Divergence, and Emerging Roles in Cytoskeletal Dynamics and Tauopathies.
    Itzhak Fischer, Peter W Baas.
      Tau proteins are microtubule-associated proteins that regulate axonal structure, dynamics, and transport, and their dysregulation underlies several neurodegenerative diseases. The MAPT gene produces multiple tau isoforms through alternative splicing, including the high-molecular-weight isoform known as Big tau, which contains an insert of the large 4a exon of approximately 250 amino acids. Big tau is predominantly expressed in neurons of the peripheral nervous system (PNS), cranial motor nuclei, and select neurons of the central nervous system (CNS) such as the cerebellum and brainstem. Developmental expression studies indicate a switch from low-molecular-weight isoforms of tau to Big tau during axonal maturation, suggesting that Big tau optimizes cytoskeletal dynamics to accommodate long axonal projections. Comparative sequence and biophysical analyses show that the exon-4a insert is highly acidic, intrinsically disordered, and evolutionarily conserved in its length but not its primary sequence, implying a structural role. Emerging modeling and in vitro assays suggest that the extended projection domain provided by the exon-4a insert spatially and electrostatically shields the aggregation-prone PHF6 and PHF6* motifs in tau's microtubule-binding domain, thereby reducing β-sheet driven aggregation. This mechanism may explain why tauopathies that involve aggregation of tau have little effect on the PNS and specific regions of the CNS such as the cerebellum, where Big tau predominates. Transcriptomic and proteomic data further suggest that alternative Big tau variants, including 4a-L, are expressed in certain cancerous tissues, indicating broader roles in cytoskeletal remodeling beyond neurons. Despite its putative anti-aggregation properties, the physiological regulation, interaction partners, and in vivo mechanisms of Big tau remain poorly defined. This review summarizes what is known about Big tau and what is missing toward a better understanding of how expansion via inclusion of exon 4a modifies tau's structural and functional properties. Our purpose is to inspire future studies that could lead to novel therapeutic strategies to mitigate tau aggregation in neurodegenerative diseases.
    Keywords:  evolutionary conservation; exon 4a; hydrophobicity; microtubule-associated protein; neurodegeneration; neurons; protein aggregation; tau
    DOI:  https://doi.org/10.3390/cells15030241
  26. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Feb 12. 1-27
    Targeting metabolic dysfunction in amyotrophic lateral sclerosis: therapeutic potential of GLP-1 receptor agonists.
    Mohamed Mohsen Helal, Nereen A Almosilhy, Dina Essam Abo-Elnour, Rana Suhail Younis Jaffal, Eman Gomaa Allam, Mohammed A Almosilhy, Suhel F Batarseh, Mostafa Meshref.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss and profound systemic metabolic dysfunction, including hypermetabolism, weight loss, insulin resistance, and altered glucose and lipid homeostasis. Increasing recognition of these metabolic abnormalities has driven interest in repurposing antidiabetic therapies, particularly glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists (GLP-1RAs), for ALS. Beyond their established metabolic actions, GLP-1RAs exert pleiotropic effects relevant to neurodegeneration, including modulation of neuroinflammation, mitochondrial function, oxidative stress, excitotoxicity, and cell-survival signaling, with selected agents demonstrating central nervous system penetration. This narrative review summarizes current knowledge on metabolic impairment in ALS and critically evaluates the mechanistic rationale, preclinical evidence, and emerging clinical data supporting or opposing the use of GLP-1-based therapies in this disease. Preclinical studies suggest that GLP-1 signaling can provide neuroprotective and neurotrophic effects in ALS models, although findings are heterogeneous and highly dependent on compound selection, delivery strategy, and experimental design. In contrast, available clinical evidence is limited and does not demonstrate therapeutic benefit in ALS, while raising important safety concerns, particularly related to weight loss, lean mass reduction, and altered glucose regulation, factors associated with a worse prognosis in ALS. Collectively, current data indicate that although GLP-1-based therapies may have compelling biological plausibility and beneficial effects in other neurodegenerative disorders (NDGs), their role in ALS remains uncertain and potentially harmful. Well-designed, ALS-specific clinical studies are required to clarify safety, efficacy, and patient selection before GLP-1RAs can be considered for therapeutic use in this vulnerable population.
    Keywords:  Amyotrophic lateral sclerosis (ALS); Exendin-4 (Ex-4); Glucagon-Like Peptide-1 (GLP-1); Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs); Hypermetabolism; Metabolic dysfunction; Motor Neurone Disease (MND); Neurodegenerative diseases (NDGs); Neuroprotection; Weight loss
    DOI:  https://doi.org/10.1080/21678421.2026.2627901
  27. Biomater Adv. 2026 Feb 03. pii: S2772-9508(26)00052-X. [Epub ahead of print]183 214754
    Ultrasound-mediated blood-brain barrier opening for targeted neurological drug delivery.
    Zibo Qin, Zhangbaihe Wang, Cancan Gao, Xueqing Yong, Yue Hua, Ying Zhou, Jinbing Xie.
      Neurological disorders represent a devastating global health crisis, and the blood-brain barrier (BBB) remains a major obstacle for their treatment. Conventional strategies for BBB opening, including direct intracranial injection, osmotic disruption, receptor-mediated transcytosis, and nanoparticle carriers, often suffers from surgical invasiveness, systemic toxicity, poor biodistribution, and off-target effects. Ultrasound-mediated drug delivery has emerged as a revolutionary non-invasive technology for transient and targeted BBB opening, enabling enhanced penetration of therapeutic agents into the central nervous system. This review comprehensively summarizes the mechanisms underlying ultrasound-based delivery with focus on current delivery platforms including microbubble (MB)-assisted, nanoparticle-based, and MB-nanoparticle composite strategies. Furthermore, we highlight recent advances in the application of focused ultrasound (FUS) combined with MBs for the treatment of Alzheimer's disease, Parkinson's disease, and glioma. Finally, we discuss emerging technologies such as sonodynamic therapy and ultrasound-controlled magnetic nanorobots, while also addressing current challenges in this field. This review underscores the transformative potential of ultrasound-mediated drug delivery as a versatile platform for precision neurology. It also prospects future directions for advancing multidisciplinary research and clinical translation.
    DOI:  https://doi.org/10.1016/j.bioadv.2026.214754
  28. Free Radic Biol Med. 2026 Feb 09. pii: S0891-5849(26)00105-X. [Epub ahead of print]
    Superoxide dismutase impacts extracellular vesicle shedding and uptake.
    Nahin Siara Prova, Malek W Elsayyid, Jessica E Tanis.
      Extracellular vesicles (EVs), which transfer bioactive macromolecules between cells, play a critical role in the pathogenesis of multiple neurodegenerative diseases. Focus has centered on how altered EV contents propagate disease and on the potential for EVs as diagnostic biomarkers, while the effects of pathogenic factors on EV release are poorly understood. Using a functional endogenous reporter, we showed that the key antioxidant enzyme superoxide dismutase 1 (SOD-1) is expressed in C. elegans EV-releasing neurons, localizes to the cytoplasm, and reduces levels of reactive oxygen species (ROS). We then defined how sod-1 mutations affect EV shedding from sensory neuron primary cilia into the environment, ciliary enrichment of proteins packaged into EVs, and glial uptake of EVs in vivo, by imaging C. elegans expressing fluorescent protein-tagged EV cargoes. Deletion of SOD-1, as well as the SOD-1(G85R) amyotrophic lateral sclerosis (ALS) pathogenic variant, increased EV shedding from the cilium distal tip, and this was associated with greater abundance of EV cargo in this ciliary compartment. In contrast, loss of SOD-1 reduced the glial uptake of a different EV subpopulation that is shed from the ciliary base, without affecting release into the environment. These results demonstrate that SOD-1 has a subtype-specific effect on the release of EVs with distinct signaling potentials. Intriguingly, we discovered that exposure to paraquat, which increases mitochondrial ROS, reduced the shedding of both distal tip and ciliary base-derived EVs. These opposing effects of the sod-1 mutations and paraquat treatment on EV release suggest that subcellular ROS compartmentalization may serve as a mechanism to regulate ciliary EV shedding.
    Keywords:  C. elegans; ROS; SOD-1; extracellular vesicles; primary cilia; superoxide dismutase
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.008
  29. Zh Nevrol Psikhiatr Im S S Korsakova. 2026 ;126(1): 132-136
    [Combination of amyotrophic lateral sclerosis with Alzheimer's disease].
    E V Pervushina, M A Kutlubaev, D R Kuznetsova, G I Karimova, O V Kachemaeva, E A Mkhitaryan.
      The combination of amyotrophic lateral sclerosis (ALS) with Alzheimer's disease is rare. Currently, it is unclear whether such comorbidity is an accidental coincidence or a manifestation of a specific pathological process. A case of simultaneous occurrence of classic symptoms of the bulbar form of ALS and Alzheimer's disease is presented. The possible mechanisms of the combination of two diseases are analyzed.
    Keywords:  Alzheimer’s disease; amyotrophic lateral sclerosis; cognitive impairment; motor neuron disease
    DOI:  https://doi.org/10.17116/jnevro2026126011132
  30. Mol Neurobiol. 2026 Feb 12. 63(1): 436
    The Impact of Zinc on Cellular Dynamics, Brain Function, and its Therapeutic Potential in Neuronal Regeneration.
    Sindhoora Bellavi Umesh, Bindu Sadanandan, Kavyasree Marabanahalli Yogendraiah, Vaniyamparambath Vijayalakshmi.
      Zinc is a vital trace element that plays a central role in maintaining brain function, regulating cellular dynamics, and promoting neuronal repair. As the second most abundant transition metal in the central nervous system, zinc is essential for neurotransmission, synaptic plasticity, and neurogenesis, processes that underlie higher cognitive functions such as learning and memory. Its homeostasis is tightly controlled, as dysregulation contributes to the onset and progression of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. At the cellular level, zinc serves as a critical regulator of proliferation, differentiation, and survival, influencing the behavior of neural and mesenchymal stem cells. Through modulation of signaling pathways such as PI3K/Akt and MAPK, zinc governs cell growth, maturation, and neuroprotection. Physiological levels support axonal sprouting, neurite extension, and synaptic connectivity, whereas excessive release under pathological conditions exacerbates oxidative stress and excitotoxicity. Emerging evidence highlights zinc's therapeutic role in neuronal regeneration. Controlled supplementation enhances neurogenesis, reduces apoptosis, restores synaptic activity, and improves memory outcomes in experimental models of neural injury. Zinc-enriched biomaterials and scaffolds are also being developed for neural tissue engineering, where the incorporation of zinc enhances neurite outgrowth, cell adhesion, and network repair. Beyond neuroregeneration, zinc-based nanomaterials are gaining biomedical significance. Zinc oxide nanoparticles (ZnO NPs) exhibit potent anticancer activity against human cancer cell lines by inducing reactive oxygen species generation, DNA damage, and apoptosis. Additionally, other zinc nanoparticles, including zinc sulfide and zinc-doped biomaterials, show potential in tissue repair, wound healing, and drug delivery applications. Collectively, these findings underscore zinc's multifaceted role in neural function, regenerative biology, and nanomedicine. Advancing our understanding of zinc-mediated mechanisms may enable the development of novel zinc-targeted therapeutic strategies for treating neurodegenerative diseases and promoting functional recovery after brain injury.
    Keywords:  Neurodegenerative diseases; Neuronal repair; Neurotransmission; Therapeutic applications; Zinc
    DOI:  https://doi.org/10.1007/s12035-026-05678-2
  31. J Nanobiotechnology. 2026 Feb 09. 24(1): 164
    A physics-informed neural network framework for quantitative analysis of transcytosis and physical diffusion in an in vitro BBB.
    Xin Wang, Bingyan Shen, Wenyuan Yang, Xiao Wang, Changwei Li, Haigang Wu.
      Nanoparticles traverse the blood-brain barrier (BBB) through passive diffusion and vesicular transcytosis, but the quantitative contributions of these routes remain difficult to determine. Here, we combine a controlled in-vitro human BBB model (hCMEC/D3 Transwells) with a physics-informed neural network (PINN) to interpret transport kinetics and estimate paracellular and vesicular components. Monodisperse polystyrene nanoparticles (20, 50 and 120 nm) showed low polydispersity, stable ζ-potential and minimal cytotoxicity. Intact monolayers displayed high TEER and low tracer permeability, whereas TNF-α induced reversible junctional opening. Apical-to-basolateral transport increased with junctional loosening and remained size-dependent; clathrin and dynamin inhibition reduced flux without altering TEER or tracer passage. A mass-balance-constrained PINN incorporating a TEER-linked permeability term reproduced transport profiles and generalized to combined perturbation (TNF-α + chlorpromazine). Under our conditions, the model suggested that vesicular uptake represented the major route, with a smaller diffusion component that increased during junctional disruption and clathrin inhibition. Overall, this combined experimental-computational approach provides a practical framework for pathway-informed evaluation of nanoparticle transport across the BBB.
    Keywords:   In vitro BBB model; Physical diffusion; Physics-informed neural networks; Transcytosis
    DOI:  https://doi.org/10.1186/s12951-026-04023-y
  32. J Clin Psychiatry. 2026 Feb 11. pii: 26f16324. [Epub ahead of print]87(1):
    The E-Value in Regression: A Useful, Simple, Easily Understood, and Easily Applied Statistic.
    Chittaranjan Andrade.
      The E-value is most simply described as the smallest strength of association that 1 or more unmeasured confounds must have with both risk factor and outcome to nullify a significant relationship between the risk factor and the outcome in a fully adjusted regression. Thus, the E-value is a measure of how robust a finding may be against unmeasured confounding. This article provides the reader with a primer on the E-value, and with a cheat sheet that simplifies concepts. The full definition of the E-value is stated, and each element in the definition is explained. The E-value is most commonly applied to statistics such as the relative risk, odds ratio, and hazard ratio but can be applied to other statistics, as well. The E-value is usually calculated for 2 estimates: the statistic that measures risk and the limit of the 95% confidence interval (CI) of the statistic that is closest to the null. The former E-value tells us how strong unmeasured confounding should be to bring the value of the statistic to null. The latter E-value tells us how strong unmeasured confounding should be to bring the null value into the 95% CI, thereby making a statistically significant finding nonsignificant. This article also explains the calculation and the interpretation of the E-value. A detailed discussion is provided on what unmeasured confounding means with reference to the E-value. The specificity of the E-value to the context of the study, and the variables adjusted for, is emphasized. Interpretation of the E-value should be based on the plausibility of existence of the unmeasured confounds and the prevalence of these confounds in the population. E-values, surprisingly, are not commonly reported. They should be reported by researchers, requested by reviewers and editors, and calculated by readers to understand how robust statistically significant findings are against unmeasured confounding.
    DOI:  https://doi.org/10.4088/JCP.26f16324
  33. Biology (Basel). 2026 Jan 26. pii: 228. [Epub ahead of print]15(3):
    New Insights on Mitochondria-Targeted Neurological Drugs.
    Silvia Lores-Arnaiz.
      Aging and neurodegenerative diseases are characterized by common features involving bioenergetics deficiencies, oxidative stress and alterations of calcium buffering. Mechanisms of mitochondrial-targeted drugs include the modulation of electron transport chain and oxidative phosphorylation, the binding to mitochondrial lipids, free-radical scavenging, calcium signaling, and possible effects on mitochondrial biogenesis and dynamics and on the regulation of mitophagic pathways. One of the main sites of action of mitochondria-targeted drugs is the interaction with respiratory chain components. Mitochondrial-targeted compounds such as Mito-Q, and Mito-apocynin have been developed by conjugating triphenylphosphonium (TPP+) lipophilic cation group with natural molecules, therefore obtaining promising drugs for reestablishing the correct functioning of the mitochondrial respiratory chain. Stabilization of cardiolipin at the inner mitochondrial membrane by elamipretide or SkQ1 and mitochondria-targeted ROS scavengers can also offer a therapeutic approach to prevent bioenergetic impairment associated with several diseases. In addition, the modulation of calcium signaling can be achieved using both MCU agonists and antagonists representing another mitochondrial target for drug therapies development. Finally, potential strategies for treating neurodegenerative diseases based on the modulation of mitochondrial biogenesis, dynamics and/or mitophagic pathways are discussed.
    Keywords:  ETC modulation; ROS scavenging; mitochondria-targeted drugs; mitochondrial function
    DOI:  https://doi.org/10.3390/biology15030228
  34. Front Immunol. 2026 ;17 1725046
    Immune crosstalk in Alzheimer's and Parkinson's disease: insights from Drosophila models into the brain-peripheral immune axis.
    Faiza Parvez, Rahul.
       Background: Neurodegenerative diseases (NDs) such Alzheimer's disease (AD) and Parkinson's disease (PD) are increasingly understood as systemic disorders driven by chronic neuroimmune dysregulation. The bidirectional communication between the central nervous system (CNS) and peripheral immune compartments is termed neuroimmune crosstalk, plays a pivotal role in disease initiation, progression, and therapeutic resistance. However, mammalian models often obscure mechanistic resolution due to immune redundancy and adaptive complexity.
    Objective: This review highlights Drosophila melanogaster as a genetically tractable and evolutionarily conserved model for dissecting innate immune signaling and inter-organ communication in neurodegeneration. We emphasize its utility in resolving causality, identifying conserved cytokine pathways, and modeling systemic inflammation relevant to Parkinson's and Alzheimer's disease.
    Key findings: Drosophila possesses a tripartite immune system that is brain-resident glia, circulating hemocytes, and the fat body that coordinates responses via Toll, Immune deficiency (Imd), JAK/STAT, and MAPK pathways. Glial cells engage in Draper-mediated phagocytosis and NF-κB/Relish signaling, while peripheral immune components modulate CNS integrity through cytokines such as Unpaired 3 (Upd3) and Eiger. Furthermore, hyperactivation of the Imd pathway's NF-κB homolog, Relish, within the CNS drives neurodegeneration via the neurotoxic effects of Antimicrobial Peptides (AMPs). These mechanisms mirror mammalian neuroimmune dynamics and reveal conserved therapeutic targets.
    Conclusion: Drosophila melanogaster offers unparalleled mechanistic clarity in modeling neuroimmune interactions. Its simplified immune architecture, precision genetics, and compatibility with multi-omics and AI-assisted phenotyping position it as a strategic complement to vertebrate models. Insights from Drosophila are redefining neurodegeneration as a multi-organ process and accelerating the development of inflammation-targeted therapies for ND.
    Keywords:  Alzheimer’s disease; Drosophila melanogaster; Parkinson’s disease; immune crosstalk; innate immunity; neurodegeneration; neuroinflammation; toll pathway
    DOI:  https://doi.org/10.3389/fimmu.2026.1725046
  35. J Neurol. 2026 Feb 11. 273(2): 140
    Treating SOD1-ALS with tofersen results in nonprogressive chronic ALS-a case series from Iceland.
    Bjorn Logi Thorarinsson, Olafur Arni Sveinsson, Agust Hilmarsson, Thora Bjorg Sigurthorsdottir, Peter Munch Andersen.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. We describe four patients with hereditary ALS caused by the p.Gly94Ser SOD1 mutation who were treated monthly with the intrathecal antisense oligonucleotide tofersen in a clinical setting at Landspitali University Hospital of Iceland. After initiating treatment 15-26 months ago, no significant clinical deterioration was observed, and three patients showed signs of clinical improvement, with some recovery of motor function. All four patients currently present with chronic nonprogressive ALS, a phenotype not previously observed or documented. Concomitantly, the concentration of neurofilament light chain (Nf-L) in the cerebrospinal fluid decreased to the normal range. This clinical benefit and decrease in Nf-L levels were detected regardless of the patient's initial ALSFRS-R score. No serious adverse events were observed. Notably, we observed a clinically meaningful effect in two patients who had been ill for several years before treatment was instituted, raising questions about who should receive treatment and the biology of paresis and motor neuron cell loss in patients with ALS. Although only a minority of ALS patients carry a SOD1 mutation, the advent of this new precision medicine has profound implications for ALS management.
    Keywords:  ALS; Antisense oligonucleotide; Neurofilament light chain; Superoxide dismutase 1; Tofersen
    DOI:  https://doi.org/10.1007/s00415-025-13579-y
  36. Nanomedicine (Lond). 2026 Feb 11. 1-22
    The application of CRISPR-Cas9 system in brain diseases.
    Yaodong Miao, Chun Li, Yadi Su, Tifang Peng, Jiaqi Wang, Shuang Liu, Chuanrui Ma, Lin Li, Yi Wang.
      As an efficient genome-editing technology, Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-CRISPR-associated protein9 (Cas9) system is increasingly being recognized as a significant therapeutic strategy for brain diseases. In recent years, researchers have continuously tried to regulate the expression of genes related to the nervous system through CRISPR-Cas9 system, which provides a new and efficient strategy for the treatment of brain diseases. At the same time, various delivery vectors of CRISPR-Cas9 system have been reported. Although some delivery vectors have not been applied to the research of brain diseases, they still provide valuable ideas for the brain delivery of CRISPR-Cas9 system. In this review, we summarized the principle of CRISPR-Cas9 system and its application in the nervous system, discussed the barrier of blood-brain barrier (BBB) to the treatment of brain diseases, overviewed various delivery vectors of CRISPR-Cas9 system and their applications, and highlighted advanced of CRISPR-Cas9 system applied to various brain diseases. Furthermore, we also discussed the existing obstacles and promising avenues for future investigation regarding CRISPR-Cas9-based therapeutic approaches. This article, through retrieving keyword combinations[PubMed,from Jan. 2018 to Dec. 2025], aims to elucidate the CRISPR-Cas9 system's potential for extensive future research and application as a therapeutic strategy for brain disorders.
    Keywords:  BBB; CRISPR-Cas9 system; CRISPR-Cas9-based treatment strategy; brain diseases; delivery vectors of CRISPR-Cas9
    DOI:  https://doi.org/10.1080/17435889.2026.2629031
  37. IMetaOmics. 2024 Dec;1(2): e33
    Emerging role of gut microbiota extracellular vesicle in neurodegenerative disorders and insights on their therapeutic management.
    Adil Hassan, Yin Huang, Mahjabina, Otmilda Hapsari Sudiro, Xiangxiu Wang, Jingqin He, Yan Wei, Xiaoling Liao, Guixue Wang.
      Targeting gut flora to lower sickness risk is a growing scientific subject. The intricate network of microorganisms (gut microbiota) in the human intestines regulates many physiological systems and may be important for general health. Recent research has shown a dynamic relationship between gut microbiota and central nervous system (CNS). Dysbiosis is key to establishing and progressing human diseases, including neurodegenerative disorders. Recently, gut microbiota extracellular vesicles (GMEVs) have been suggested as brain-gut communication carriers. Vesicle components contact immune receptors, initiating neuroinflammatory immune responses and causing neurodegenerative diseases. This study seeks to explain how the gut microbiota and its extracellular vesicles cause or worsen neurodegenerative diseases. We also highlighted recent advances in our understanding of these GMEVs' and cargo's routes, which could be used in drug delivery treatments. This study also examines the current state and potential therapeutic effects of GMEVs on neurodegenerative illnesses.
    Keywords:  brain dysfunction; drug delivery system; gut microbiota extracellular vesicle; neurodegenerative disorders; neuro‐inflammation
    DOI:  https://doi.org/10.1002/imo2.33
  38. Front Neurol. 2025 ;16 1737468
    CRISPR-Cas technologies in neurodegenerative disorders: mechanistic insights, therapeutic potential, and translational challenges.
    Raya Kh Yashooa, Ari Q Nabi, Shukur Wasman Smail, Sarkar Sardar Azeez, Wissam Albeer Nooh, Suhad A Mustafa, Abd Al-Bar Al-Farha, Nazzareno Capitanio, Mudhir Sabir Shekha.
      CRISPR-Cas genome-editing technologies have emerged as powerful tools for precise DNA and RNA modulation, offering promising therapeutic strategies for neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). This review critically evaluates current CRISPR/Cas applications in neurodegeneration, with emphasis on mechanistic insights, therapeutic outcomes, and translational feasibility. Preclinical and early translational studies demonstrate that CRISPR-Cas platforms can correct pathogenic mutations, suppress toxic gene expression, and restore neuronal function. Advanced modalities, including base and prime editing, CRISPRi/a, and RNA-targeting Cas systems, improve precision and reduce genomic damage, which is particularly advantageous in post-mitotic neurons. Emerging CRISPR-based diagnostics (e.g., SHERLOCK and DETECTR), AI-assisted sgRNA design, and machine-learning approaches for predicting off-target effects further enhance the safety, stratification, and monitoring of CRISPR therapeutics. In parallel, patient-derived brain organoids and assembloids provide scalable human-relevant platforms for mechanistic studies and preclinical validation. Despite this progress, major challenges remain, including efficient delivery across the blood-brain barrier, immune responses, long-term safety, and ethical and regulatory considerations. Overall, CRISPR-Cas technologies hold strong potential as disease-modifying interventions for neurodegenerative disorders, provided that advances in delivery systems, artificial intelligence integration, and regulatory oversight continue to evolve toward clinical translation.
    Keywords:  CRISPR–Cas; applications; challenges; neurodegenerative disorders; therapeutic strategies
    DOI:  https://doi.org/10.3389/fneur.2025.1737468
  39. J Cereb Blood Flow Metab. 2026 Feb 08. 271678X261418925
    Airborne particulates and brain health: The role of PM2.5 in blood-brain-barrier dysfunction.
    Fátima Gimeno-Ferrer, Lisa Teresa Porschen, Frank Matthes, Katrin Gohlsch, Anja Meissner.
      Ambient particulate matter (PM), especially fine and ultrafine particles, has emerged as a significant environmental risk factor for neurological disorders, largely through its impact on the blood-brain barrier (BBB) and the neurovascular unit. This review summarizes current evidence on how PM affects BBB integrity, emphasizing the coordinated and cell-specific responses that drive neurovascular dysfunction. Upon systemic or neural translocation, PM induces oxidative stress and inflammation in endothelial cells, disrupting tight junctions (TJs), enhancing permeability, and upregulating adhesion molecules (e.g. ICAM-1 and VCAM-1), which facilitate immune cell infiltration. Pericytes contribute to these processes in a stage-dependent manner, promoting BBB leakage through detachment and inflammation in acute settings while participating in later reparative processes such as angiogenesis and neurogenesis. Astrocytes respond to PM exposure by adopting a reactive phenotype, releasing pro-inflammatory cytokines and reactive oxygen species that exacerbate barrier disruption and impair neurovascular coupling. Microglia act as central mediators of neuroinflammation, releasing cytokines that weaken TJs and perpetuate endothelial dysfunction. These mechanisms are further modulated by particle properties and host-related factors including age, metabolic status, and pre-existing comorbidities. The resulting cascade of BBB impairment and neuroinflammation underscores the multifaceted nature of PM-induced neurotoxicity and identifies potential cellular targets for intervention.
    Keywords:  Particulate matter; blood–brain barrier; neuroinflammation; oxidative stress
    DOI:  https://doi.org/10.1177/0271678X261418925
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