bims-barned 2026-02-22 papers

bims-barned

Biomed News

on BBB and Neurodegeneration-ALS

Issue of 2026–02–22
twenty-two papers selected by
Luca Bolliger, lxBio

Metabolic interactions in the brain: the crucial roles of neurons, astrocytes, and microglia in health and disease.
Targeting gut-brain-immune axis in amyotrophic lateral sclerosis.
Timing of communication and technology control support in ALS - a systematic review.
The Role of the Golgi Apparatus in Neurodegeneration.
Interactions of bile acids and gut microbiota modulate neurological health: a comprehensive review on mechanisms and therapeutic potential of dietary phytochemicals.
Neurorehabilitation in the 21st Century: New Science, New Strategies, New Expectations.
Molecular insights into glial neuroimmune cross reactivity with CNS antigens and its role in neuroinflammation.
Neuro-renin-angiotensin-aldosterone system axis in alzheimer's disease: from molecular dysregulation to therapeutic redirection.
Predictive genetic testing in amyotrophic lateral sclerosis (ALS): Experiences of decision-making and engagement with UK genetic counseling services.
The immune-metabolism interactome in efferocytosis: a new paradigm for the central nervous system diseases revealed by single-cell sequencing analysis.
The crosstalk between blood-brain barrier and neural cells: bidirectional regulation of brain function and pathology.
Probiotic and microbial modulation of polyamine production: an emerging avenue for neuroprotection in neurodegenerative disorders.
The Dynamic Role of the Golgi Apparatus in Neuronal Function and Alzheimer's Disease.
Glial cells in dementia: From cellular dysfunction to therapeutic frontiers.
Exploratory analysis of smartphone-based step counts as a digital biomarker for survival in ALS patients.
An integrative neurogenomics workflow for precision medicine in neurodegenerative disorders.
In vitro models of microbiota-gut-brain axis communication at the blood-brain barrier interface.
Pantothenic Acid and Parkinson Disease: A Systematic Review of Metabolomics Analysis Studies.
Therapeutic targeting of neuroimmune mechanisms in neurodegeneration.
Gut microbiota: new links between exercise and disease.
The human and murine immune systems: regulated by dichotomous molecules.
C9orf72-derived dipeptide repeat proteins poly-PR disrupt membrane excitability and synaptic function in cortical neurons.

Front Neurosci. 2026 ;20 1731771

Metabolic interactions in the brain: the crucial roles of neurons, astrocytes, and microglia in health and disease.

Yonghui Pang, Jiachen Yang, Jingjing Liu, Zhengyi Xie, Jin Wang.

  This review provides an in-depth exploration of the intricate energy metabolism pathways within the brain, with a particular focus on the dynamic interplay between neurons, astrocytes, and microglia. Neurons, with their high energy demands, primarily rely on oxidative phosphorylation and the tricarboxylic acid (TCA) cycle to sustain synaptic activity and neurotransmitter synthesis. In contrast, astrocytes predominantly engage in glycolysis, producing lactate and glutathione, which are essential for supporting neuronal function and protecting against oxidative stress. Additionally, microglia, the brain's resident immune cells, exhibit a metabolic flexibility that allows them to shift between oxidative phosphorylation and glycolysis, depending on their activation state, which significantly influences neuroinflammation and synaptic plasticity. The review highlights the critical role of astrocyte-neuron metabolic coupling, particularly through the lactate shuttle and glutathione metabolism, in maintaining neuronal homeostasis and facilitating synaptic function. It also delves into the metabolic underpinnings of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis, illustrating how disruptions in brain energy metabolism contribute to disease progression. By synthesizing recent findings, this review not only underscores the centrality of brain energy metabolism in both normal and pathological conditions but also identifies potential therapeutic targets aimed at modulating these metabolic pathways to mitigate the effects of neurodegenerative disorders. This comprehensive analysis offers valuable insights that could propel further research and innovation in the field of neurology, making it essential reading for experts interested in the molecular mechanisms underlying brain function and disease.

Keywords:  astrocytes; disease; homeostasis; metabolism; microglia; neurons

DOI:  https://doi.org/10.3389/fnins.2026.1731771
Front Immunol. 2025 ;16 1637976

Targeting gut-brain-immune axis in amyotrophic lateral sclerosis.

Naga Sriharsha Mudda, Lucas Zhang, Pooja Sampelli.

  Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron neurodegenerative disorder with a median survival of only 3-5 years. The heterogeneity of the disease and lack of effective therapies highlight the importance of identifying novel pathogenic mechanisms. We hypothesize that dysbiosis of gut microbiota enhances ALS by disrupting intestinal barrier function and altering metabolite profiles to drive systemic inflammation and neuronal stress. Precisely, the decrease in health-promoting bacteria (e.g., Akkermansia muciniphila, Bifidobacterium and Lactobacillus spp.) in ALS can reduce neuroprotective metabolite production (short-chain fatty acids, nicotinamide, GABA, precursors of serotonin) and increase gut permeability, enabling lipopolysaccharide (LPS) and pro-inflammatory cytokines into the circulation. Such changes would activate microglia and impair motor neuron homeostasis by glutamate excitotoxicity and mitochondrial dysfunction. The gut-brain axis operates through immune-mediated mechanisms, where ALS-associated microbiota changes compromise mucosal immunity and trigger peripheral Th1/Th17-biased responses with impaired Treg regulation. Elevated endotoxin levels correlate with TLR4-driven inflammation, promoting pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) that cross into the CNS and prime microglia toward a neurotoxic M1 phenotype, creating a milieu where IL-17A and other mediators directly injure motor neurons. Our hypothesis relies on establishing human and animal evidence of microbiome derangements, barrier dysfunction, and immune deregulation with ALS. We hypothesize that restoration of an "ALS-protective" microbiota consortium or its metabolic by-products can potentially slow disease progression. Testable hypotheses include improvement of ALS model motor deficits by probiotic or fecal-microbiota therapies, and normalization of inflammatory biomarkers. This paradigm recontextualizes ALS as a gut-brain disease and suggests new directions for translational research into this unmet medical indication.

Keywords:  SCFAs; amyotrophic lateral sclerosis; gut-brain axis; immune system; inflammation; microbiome; neurodegeneration; nicotinamide

DOI:  https://doi.org/10.3389/fimmu.2025.1637976
Amyotroph Lateral Scler Frontotemporal Degener. 2026 Feb 20. 1-9

Timing of communication and technology control support in ALS - a systematic review.

Simon Judge, Kirsty Ballesteros, Christopher J McDermott, Steven Bloch.

  Objective: To review evidence on the optimal timing of interventions that support communication and technology control for people living with Amyotrophic Lateral sclerosis (ALS). Methods: A systematic review was conducted following a pre-registered protocol. Databases were searched for studies involving people living with ALS that addressed timing of assistive technology interventions for communication or technology control. Screening and data extraction were completed in duplicate, findings were synthesized using a thematic analysis, and relevant findings presented as a descriptive summary. Results: Twenty-eight studies met the inclusion criteria. Evidence focused overwhelmingly on communication support rather than wider assistive technology interventions. Need for a communication aid typically occurs between one and five years from diagnosis and the timing of this varies significantly according to the site of onset of ALS. There are significant variations in the timing of changes for individuals within these groupings and there are likely a larger number of groupings that would be clinically useful. A significant correlation between changes in speaking rate and intelligibility has been shown. Once changes to speech do start to occur then the time to the loss of functional speech appears relatively consistent across the types of ALS. Conclusion: Current best practice guidelines are not reflective of the findings of this review and do not support professionals in identifying how to provide timely support. Monitoring speech changes systematically may support timely intervention. There is potential for individual level predictive modeling to help support people living with ALS to be proactive and prepared for changes.

Keywords:  Motor neuron disease; amyotrophic lateral sclerosis; assistive technology; augmentative and alternative communication; intervention; timing

DOI:  https://doi.org/10.1080/21678421.2026.2627899
Subcell Biochem. 2026 ;111 413-440

The Role of the Golgi Apparatus in Neurodegeneration.

Sina Shadfar, Sara Assar Kashani, Shashi Gautam, Zeinab Takalloo, Fabiha Farzana, Sonam Parakh, Julie D Atkin.

  The Golgi apparatus has important, well characterised functions in the trafficking, processing, and post-translational modification of proteins and lipids. However, roles in other cellular processes are increasingly reported, including autophagy, apoptosis, DNA repair, and cytoskeletal (microtubules and actin) function. The Golgi therefore serves as a regulatory hub for multiple signalling pathways that maintain essential cellular activities. The Golgi normally consists of flattened stacks of membrane (cisternae), but during normal physiology and pathological conditions it 'fragments', resulting in altered morphology and distribution. This is well described as an early pathological feature of many neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) and prion diseases, and amyotrophic lateral sclerosis (ALS). These age-related conditions are characterised by the death of neurons: highly specialised, unique cells that form the foundation of the nervous system. Interestingly, many Golgi-related functions are also dysregulated in these diseases. However, this has received relatively little attention compared to other pathogenic mechanisms. The Golgi apparatus in neurons shares features common to other eukaryotic cells but it also has unique properties, such as the presence of distinctive assemblies: Golgi outposts and satellites, which remain poorly characterised. Here we discuss the increasing evidence describing dysfunction and fragmentation of the Golgi apparatus and its possible role in the pathogenesis of neurodegenerative diseases.

Keywords:  Golgi apparatus; Golgi outposts; Neurodegeneration; Neurodegenerative diseases; Neurons; Vesicular transport

DOI:  https://doi.org/10.1007/978-3-032-16833-7_17
Front Microbiol. 2026 ;17 1757551

Interactions of bile acids and gut microbiota modulate neurological health: a comprehensive review on mechanisms and therapeutic potential of dietary phytochemicals.

Jie Wang, Ying Zhang, Quan Wu, Yingfu Zhong, Ze Xu, Juan Yang.

  Bile acids (BAs), classically regarded as detergents for dietary lipid absorption, have emerged as pivotal signaling molecules with systemic endocrine functions. The discovery of the Farnesoid X Receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) as BAs-activated receptors unveiled their profound influences on glucose, lipid, and energy metabolism. BAs are first synthesized in hepatocytes and further metabolized by gut microbes, can either circulate in enterohepatic system or be found in circulations to exert various effects. More recently, the gut-brain axis has been identified as a critical pathway through which BAs exert significant effects on central nervous system (CNS) function and health. Based on research progresses mentioned above, this review systematically delineates the synthesis, metabolism, and classification of BAs, with a focus on the intricate crosstalk between the hepatic-gut BA axis and the brain. In addition, we explore the compelling evidences linking BAs dysregulation to a spectrum of neurological disorders, including neurodegenerative diseases (Alzheimer's and Parkinson's disease), depression, and hepatic encephalopathy. Besides, the potential mechanisms, such as alleviating neuroinflammation, maintaining the integrity of blood-brain barrier, increasing the neuronal survival, and modulating neurotransmitter systems are further elucidated. Finally, strategies of dietary intervention through phytochemicals to modulate the BAs pool for improved neurological outcomes are summarized and discussed. By integrating pre-clinical and clinical findings, this review aims to establish a foundation for understanding BAs as novel therapeutic targets in neurology and nutritional neuroscience.

Keywords:  bile acids; gut-brain axis; microbiome; neuroinflammation; neurological health; phytochemicals

DOI:  https://doi.org/10.3389/fmicb.2026.1757551
Neurorehabil Neural Repair. 2026 Feb 16. 15459683251412309

Neurorehabilitation in the 21st Century: New Science, New Strategies, New Expectations.

Jonathan R Wolpaw, Aiko K Thompson, Monica A Perez, Sumner L Norman, Martin Oudega, Carolee J Winstein.

  BackgroundNeurorehabilitation is among the most vibrant areas of biomedical research. Its main strategy has been skill-specific practice, which often fails to produce adequate recovery. Now, new recognition of central nervous system (CNS) plasticity, new understanding of skills, and new technologies provide new strategies that enhance the efficacy of practice.ObjectivesThe substrate of a skill is a network of neurons and synapses that extends from cortex to spinal cord and is now called a heksor. A heksor changes continually to maintain the key features of its skill, the attributes that make the skill satisfactory. Muscle activity and kinematics may change; key features are maintained. Heksors share neurons and synapses. Through their concurrent changes, they keep the CNS in a negotiated equilibrium that enables each to maintain its skill. When CNS damage occurs, the goal is to enable damaged heksors to repair themselves.ResultsTwo new strategies enhance the efficacy of skill-specific practice. One increases plasticity. A damaged heksor shapes the additional plasticity through practice. The other targets beneficial plasticity to a critical site in a damaged heksor. This improves practice, enabling the heksor to achieve wider beneficial plasticity. In animals and humans, protocols that combine these strategies with practice enhance lasting recovery.ConclusionsThe challenge is to develop, optimize, and validate these combined protocols. Computational modeling can accelerate the process. Controlled trials and comprehensive outcome assessments are essential. Pre-morbid factors and physiological measures may identify biomarkers that can predict efficacy or guide patient-specific protocol design. Many combined protocols will be noninvasive and suitable for home use.

Keywords:  brain injury; heksor; neuroplasticity; neurotechnology; spinal cord injury; stroke

DOI:  https://doi.org/10.1177/15459683251412309
Inflammopharmacology. 2026 Feb 19.

Molecular insights into glial neuroimmune cross reactivity with CNS antigens and its role in neuroinflammation.

Anil Kumar Yadav, Priyanka Verma, Ashish Srivastava, Parul Srivastava, Rohit Rai, Shubham Rathour.

  Neuroinflammation has been increasingly considered a key player of neurodegenerative as well as psychiatric disorders. This review integrates existing knowledge on glial-neuroimmune interactions, emphasizing the roles of cytokine signaling, glial activation, and BBB modulation in neuro-pathogenesis. A systematic review was performed studying peer-reviewed literature on molecular pathways of microglia, astrocytes, endothelial cells, and peripheral immune mediators. A possible explanation of this finding could be that the model is based on the underlying pathophysiology, and this is shared across disease contexts, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury. Novel in vitro platforms, including the organ-on-a-chip and brain organoids, were also discussed for their translational potential. Microglia M1/M2 polarization and astrocyte reactivity appeared to be a common feature in neurotoxicity as well as excitotoxicity and chronic inflammation. Cytokine cascade of TNF-α, IL-1β, and IL-6 led to the disrupted BBB, allowing for peripheral immune cells to infiltrate. Both the NLRP3 inflammasome and mitochondrial dysfunction were identified as enhancers of neuroimmune signaling. Comparing across disease models, shared relationships emerged between glia-cytokines-BBB. Advanced in vitro systems proved to be useful to model these interactions and screen prescription drugs. This review highlights existing insights into glia-neuroimmune cross-reactivity and its critical role in CNS disease. The molecular interactions between these molecules could represent promising targets for novel therapeutic options. We suggests integrative systems platforms and AI-driven strategies to expedite clinical translation in neuroinflammation.

Keywords:  Blood–brain barrier; Cytokines; Glial activation; NLRP3 inflammasome; Neurodegeneration; Neuroinflammation

DOI:  https://doi.org/10.1007/s10787-026-02113-9
Metab Brain Dis. 2026 Feb 18. 41(1): 36

Neuro-renin-angiotensin-aldosterone system axis in alzheimer's disease: from molecular dysregulation to therapeutic redirection.

Gursimran Singh, Kousik Maparu, Khadga Raj Aran.

  Alzheimer's disease (AD) is characterized by progressive neurodegeneration marked by tau hyperphosphorylation, amyloid-beta (Aβ) buildup, neuroinflammation, and blood-brain barrier (BBB) dysfunction. Although much attention is paid to understanding amyloid and tau pathologies, there are still no disease-modifying solutions. Recent evidence indicates that the brain-specific Renin-Angiotensin-Aldosterone System (RAAS), conventionally involved in the regulation of cardiovascular diseases, could be central in controlling the key neuropathological alterations in AD. This review explains the binary roles of the classical (ACE/Ang II/AT₁R) and alternative (ACE 2 /Ang-(1-7)/MasR) axis of the RAAS in the central nervous system (CNS), including how overactivation of the classical axis intensifies oxidative stress and Aβ plaque formation, tau hyperphosphorylation, and BBB disruption, and how the alternative axis is neuroprotective, anti-inflammatory, and vasodilatory effects. We integrate molecular, cellular, and translational information about RAAS-mediated regulation of neurovascular integrity, glial activation, and synaptic resilience. We also discuss the repurposing of centrally acting ACE inhibitors and angiotensin II receptor blockers (ARBs), as well as next-generation MasR agonists and recombinant ACE2, as promising tools to re-establish neuro-RAAS balance. These findings together support a paradigm shift of the RAAS as a system-level therapeutic axis in AD. Conclusively, there is a need to highlight the necessity of specific CNS biomarkers and the accuracy of medicine models that can direct interventions on RAAS-related actions and redesign AD administration beyond symptom resolution to modify the disease.

Keywords:  ACE; Alzheimer’s disease; MasReceptor; Neuroinflammation; RAAS

DOI:  https://doi.org/10.1007/s11011-025-01780-x
J Genet Couns. 2026 Feb;35(1): e70184

Predictive genetic testing in amyotrophic lateral sclerosis (ALS): Experiences of decision-making and engagement with UK genetic counseling services.

Jade Howard, Hilary L Bekker, Christopher J McDermott, Alisdair McNeill.

  Predictive genetic testing enables at-risk relatives of people with amyotrophic lateral sclerosis (ALS, also known as motor neuron disease or MND) to find out if they have inherited the genetic variant identified in their family member and have an increased chance of developing symptoms. As research progresses, eligibility for and interest in predictive testing is increasing. This paper explores the experiences of people making decisions about predictive testing and identifies their information needs over the process. Semi-structured interviews were carried out with 14 individuals from across the United Kingdom who had, or were considering, predictive testing for ALS. Interviews were carried out via video call or face-to-face between March and September 2023, transcribed, and analyzed using inductive framework analysis. Findings illustrate a range of experiences. Interviews suggest variation in practice in terms of the structure of the genetic counseling process and the content of information given. Some expressed positive experiences of genetic counseling, and valued feeling listened to, understood, and supported. Others perceived barriers to accessing testing, felt the information provided was directive or not sufficient to support their concerns and decision-making. Information needs varied, and whilst people felt satisfied, there were also diverse, unmet information and support needs raised throughout the decision-making process and beyond. This evidence has been used to support the development of a patient decision aid for predictive genetic testing in ALS.

Keywords:  amyotrophic lateral sclerosis; decision‐making; information needs; motor neuron disease; predictive genetic testing; qualitative research

DOI:  https://doi.org/10.1002/jgc4.70184
J Pathol. 2026 Feb 16.

The immune-metabolism interactome in efferocytosis: a new paradigm for the central nervous system diseases revealed by single-cell sequencing analysis.

Huiyi Zhang, Wenbin Li, Peilun Xiao, Zeyao Lu, Ye Tian, Ying Xu.

  Efferocytosis is a process that maintains tissue homeostasis by removing apoptotic cells (ACs) by professional or non-professional phagocytes. The intricate process can be categorized into recognition of ACs, engulfment of ACs, and degradation of efferosomes. Aberrations in efferocytosis result in inadequate clearance of ACs, leading to prolonged inflammation that is implicated in the development and progression of various human diseases. Most central nervous system (CNS) diseases are associated with dysregulation of inflammatory homeostasis. Microglia, the resident immune cells of the CNS, play a primary role in efferocytosis in the brain, which is essential for maintaining the homeostasis of the internal environment. In this review, we summarize the current knowledge of the basic processes of efferocytosis and its indispensable role in the developing and aging brain. Additionally, we discuss the regulatory role of immune-metabolism crosstalk and the insights from single-cell sequencing analysis in dissecting microglial heterogeneity during efferocytosis. We also focus on recent discoveries regarding the critical role of efferocytosis in several CNS diseases, including cerebral ischemia, intracerebral hemorrhage, traumatic brain injury, major depressive disorder, glioblastoma multiforme, Alzheimer's disease, and Parkinson's disease. Finally, we outline potential therapeutic strategies and existing challenges, emphasizing the need for context-specific targeting to improve CNS disease outcomes. © 2026 The Pathological Society of Great Britain and Ireland.

Keywords:  apoptosis; central nervous system; efferocytosis; immune metabolism; inflammation

DOI:  https://doi.org/10.1002/path.70031
Biochem Biophys Rep. 2026 Mar;45 102475

The crosstalk between blood-brain barrier and neural cells: bidirectional regulation of brain function and pathology.

Manling Ju, Haozhou Shen, Xiaobao Zhang, Mi Tian, Li Zhang.

  The blood-brain barrier (BBB) serves as a crucial interface between the circulatory system and the central nervous system (CNS), playing a fundamental role in preserving normal brain function and homeostasis.The BBB closely interacts with various neural cells. However, the bidirectional communication between the BBB and neural cells remains incompletely understood. This review investigates the interactions between BBB and neural cells- pericytes neurons, astrocytes, microglia, oligodendrocytes and oligodendrocytes-specifically examining their functions in maintaining BBB structural integrity and barrier function. We further summarize the molecular mechanisms underlying BBB dysfunction in neurological diseases and highlight the role of BBB-neural cell crosstalk in these conditions. Moreover, we emphasize the importance of further studies to clarify how neural cells precisely regulate BBB integrity, tailor individualized treatment strategies, and improve outcomes for neurological disorders. Such advancements would provide valuable insights for both ongoing research and clinical practice.

Keywords:  Blood-brain barrier; Cellular interactions; Neural cell; Neuroinflammation; Neurological diseases

DOI:  https://doi.org/10.1016/j.bbrep.2026.102475
Amino Acids. 2026 Feb 21.

Probiotic and microbial modulation of polyamine production: an emerging avenue for neuroprotection in neurodegenerative disorders.

Tushar Adhikari, Prerona Saha.

  Neurodegenerative disorders are an Critical worldwide issue, characterized by progressive neuronal loss and cognitive decline with limited effective therapies. A central problem in these conditions is chronic neuroinflammation, oxidative stress, and disrupted cellular homeostasis. Polyamines, such as putrescine, spermidine, and spermine-small molecules-play vital roles in maintaining neuronal function, regulating autophagy, and protecting against cellular stress. Notably, spermidine-induced autophagy has emerged as a key mechanism linking polyamine metabolism to neuronal longevity and cognitive resilience. Recent studies highlight that probiotics and specific gut microbes can effectively modulate host polyamine production through the gut-brain axis, influencing neural health. This microbial modulation has been shown to restore polyamine balance, enhance antioxidant defenses, and reduce neuroinflammatory responses. Targeting microbiota-driven polyamine synthesis is emerging as a promising, non-invasive approach for neuroprotection. This review consolidates the current understanding of polyamine biology and microbial influences, highlighting their therapeutic potential. Exploring these interactions offers new avenues for innovation in combatting neurodegenerative disorders.

Keywords:  Autophagy; Gut–brain axis; Microbial modulation; Neurodegenerative disorders; Neuroinflammation; Neuroprotection; Oxidative stress; Polyamines; Probiotics; Spermidine

DOI:  https://doi.org/10.1007/s00726-026-03505-5
Subcell Biochem. 2026 ;111 441-462

The Dynamic Role of the Golgi Apparatus in Neuronal Function and Alzheimer's Disease.

Lou Fourriere, Paul A Gleeson.

  The Golgi apparatus is a highly dynamic organelle and central to the regulation of a variety of cell processes. Here we review the relationship between the morphology and function of this organelle, especially to in relation to neuronal development and maintenance. The morphology of the Golgi organelle in neurons is unique as it is present as a Golgi ribbon in the cell body and also as dendritic Golgi elements, known as Golgi outposts, in the neuronal extensions. Many neurodegenerative diseases are associated with the loss of the Golgi ribbon structure and the appearance of dispersed and fragmented Golgi units in the cell body/soma. Here we summarise a key role of the Golgi to limit the proteolytic processing of amyloid precursor protein (APP) by secretases and protect healthy cells, and the perturbations of Golgi morphology arising from increased APP processing and amyloid β production in Alzheimer's disease, the most common of the neurodegenerative disease. The potential consequence of changes in the Golgi architecture and increase of amyloid β production on neuronal function is also considered.

Keywords:  Alzheimer’s disease (AD); Amyloid precursor protein (APP); Amyloid β; Golgi apparatus; Golgi outposts; Golgins; Membrane trafficking; Mini-stacks

DOI:  https://doi.org/10.1007/978-3-032-16833-7_18
Cell Transplant. 2026 Jan-Dec;35:35 9636897251414216

Glial cells in dementia: From cellular dysfunction to therapeutic frontiers.

Hassan Jubair.

  Neurodegenerative dementias, including Alzheimer's disease and vascular dementia, have long been viewed through a neuron-centric lens. However, growing evidence highlights the indispensable and multifaceted roles of glial cells, astrocytes, microglia, and oligodendrocytes in both the onset and progression of these disorders. While prior reviews have cataloged glial dysfunction in isolation, this review offers a novel, integrative framework that maps the interconnected roles of glial subtypes across molecular, cellular, and circuit-level pathology in dementia. We critically synthesize recent advances in single-cell RNA sequencing, spatial transcriptomics, and glial imaging to redefine glial heterogeneity and function in disease states. Special emphasis is placed on the dynamic cross talk between glial populations and the feedback loops that govern their dual roles in neuroprotection and neurodegeneration. Furthermore, we examine emerging therapeutic strategies targeting glial-specific pathways, including NF-κB, JAK/STAT, CSF1R, and TREM2 signaling, as well as remyelinating agents and stem cell-based interventions. By integrating glial biology with therapeutic innovation, this review positions glial cells not as supporting actors but as central regulators and potential gatekeepers of dementia pathogenesis and treatment.

Keywords:  Alzheimer’s disease; glial cells; microglia modulation; neuroinflammation; remyelination therapy; single-cell RNA sequencing; vascular dementia

DOI:  https://doi.org/10.1177/09636897251414216
Front Digit Health. 2025 ;7 1705368

Exploratory analysis of smartphone-based step counts as a digital biomarker for survival in ALS patients.

Marcos Matabuena, Marcin Straczkiewicz, Narghes Calcagno, Katherine M Burke, Timothy B Royse, Amrita Iyer, Kendall T Carney, Sydney Hall, James D Berry, Jukka-Pekka Onnela.

  Amyotrophic lateral sclerosis (ALS) is a progressive and debilitating neurodegenerative disease. Digital biomarkers derived from smartphone data can enable scalable, low-cost, remote, unobtrusive, and quantitative measurement of physical activity (PA). These biomarkers offer opportunities for quasi-continuous assessment of PA levels, which may provide new methods for monitoring ALS disease progression in real time. In this exploratory study, we analyzed data from 31 individuals with ALS (including 16 deaths) with up to 9 years of follow-up (median 3 years) to assess the impact of incorporating smartphone-derived PA measures into survival prediction models. We examine whether the strength of the statistical association with survival differs when PA is summarized as (i) a simple metric, such as the mean daily step count, vs. (ii) distributional representations of PA. The exploratory results suggest that the addition of PA variables defined via distributional representations improves the performance of the model, as reflected by higher C-score values ( 0.68 vs. 0.55 , estimated as the median over bootstrap replicas B=1,000 ). A bootstrap-based hypothesis test shows statistically significant differences between the two models at the confidence level of 90%. These exploratory results indicate that the use of more advanced metrics to summarize PA time series can produce more accurate digital biomarkers to monitor the progression of ALS, although larger studies with larger sample sizes are required to confirm these findings.

Keywords:  accelerometry; amyotrophic lateral sclerosis; digital biomarkers; distributional data analysis; physical activity; smartphone; survival analysis

DOI:  https://doi.org/10.3389/fdgth.2025.1705368
Front Dement. 2026 ;5 1745504

An integrative neurogenomics workflow for precision medicine in neurodegenerative disorders.

Carlos Perezcano, Mariana Pérez-Coria.

  Neurodegenerative diseases represent an expanding global health challenge, with rapidly increasing prevalence and substantial economic impact. The therapeutic clinical approach continues to seek solutions through pharmacological means-such as inhibitors and antibodies-which, while sometimes controlling symptoms, have not addressed the underlying pathophysiology. By integrating advanced genomics with selected biochemical markers, under the continuous oversight of a multidisciplinary team working in consensus, it is possible to achieve a more comprehensive understanding of individual phenotypes, enabling the design of truly personalized neurogenomics-based functional plans. This article outlines the steps of the proposed integrative neurogenomics workflow, discussing its advantages and limitations, and presents highlights from an illustrative case intended as a potential reference model to establish the foundation for a new standard of personalized genomic medicine in neurodegeneration. The workflow underscores the importance of considering the additive burden of genetic variants typically classified as benign-beyond the ACMG pathogenicity framework-for accurate phenotypic assessment. It further demonstrates the feasibility of developing actionable and highly precise functional interventions by integrating genomic and biochemical data. Findings from the case example reveal correlations between genetic variants and biochemical markers, providing the basis for personalized recommendations in nutrition, lifestyle, and supplementation. This framework aims to establish the foundations of personalized genomic medicine in neurodegenerative diseases, underscoring the urgent need to move beyond one-size-fits-all approaches.

Keywords:  Alzheimer; dementia; genomics; integrative workflow; neurodegenerative diseases; precision medicine

DOI:  https://doi.org/10.3389/frdem.2026.1745504
J Cereb Blood Flow Metab. 2026 Feb 16. 271678X261419964

In vitro models of microbiota-gut-brain axis communication at the blood-brain barrier interface.

Maya R Davies, Courtney B Cross, María Rodriguez Aburto, John F Cryan, Hannah R Wardill.

  Microbiota-gut-brain axis dysfunction is increasingly implicated in the development of various neuropathologies. The blood-brain barrier (BBB) serves as a critical interface between the central nervous system (CNS) and the systemic milieu, modulated by the gut microbiota and associated secretome. Increasingly, the therapeutic potential of microbial metabolites, such as short-chain fatty acids (SCFAs), in reducing BBB disruption and mitigating neuropathologies across multiple neurological conditions has been explored. However, research methodologies remain inconsistent, owing to a lack of clarity on how to effectively model microbiota-gut-brain interactions at the BBB interface. In order to fully realise the potential of the microbiota-gut-brain axis it is crucial to adopt best-practice study designs alongside ongoing advancements in biotechnology that enable more biologically relevant modelling of this complex system. In this review, we examine current knowledge on the role of the BBB in mediating microbiota-gut-brain interactions and explore both established and emerging methods used to study these processes.

Keywords:  Blood–brain barrier; in vitro; microbiota-gut-brain axis; modelling; short chain fatty acids

DOI:  https://doi.org/10.1177/0271678X261419964
Nutr Rev. 2026 Feb 19. pii: nuaf232. [Epub ahead of print]

Pantothenic Acid and Parkinson Disease: A Systematic Review of Metabolomics Analysis Studies.

Sorayya Kheirouri, Mohammad Alizadeh.

   CONTEXT: The protective effects of vitamins on the dopaminergic neurons and against alpha-synuclein toxicity indicate their possible contribution to Parkinson disease (PD) pathogenesis. Suboptimal status of pantothenic acid could play a potential role in neurodegeneration through impairment of coenzyme A synthesis.
OBJECTIVE: In this study we aimed to summarize the available evidence concerning the link between pantothenic acid and the risk of PD.
DATA SOURCES: We searched the databases of PubMed, SCOPUS, Web of Science, and Google Scholar with no date restrictions up to June 2025 to find original published literature on the relationship between pantothenic acid and PD.
DATA EXTRACTION: We eliminated duplicated or unrelated studies and critically evaluated the findings of the screened studies, summarizing them descriptively. We also investigated possible mechanistic pathways relating to the connection between pantothenic acid and the risk of PD.
DATA ANALYSIS: Of the 1208 citations obtained, 19 articles (3 dietary assessments and 16 metabolomics analysis studies) were included in the final review. Two out of 3 studies showed that high dietary consumption of pantothenic acid was associated with decreased odds of PD. Of 16 studies that performed metabolomics analysis of biofluids, brain structures, and fecal samples, all studies reported the recognition of pantothenic acid as an altered metabolite in PD patients compared with controls (reduced level, n = 12; increased level, n = 2; disturbed pathway, n = 2) and the identification of pantothenic acid as a metabolite that may be useful for differentiating the PD group from the healthy group.
CONCLUSION: According to most of the evidence reported in this review, reductions in pantothenic acid levels or alterations of the pantothenate-coenzyme A biosynthesis pathway may be instrumental in the etiopathology of PD.The protocol of this study was registered and approved by the Deputy for Research and Technology, Tabriz University of Medical Sciences (IR.TBZMED.VCR.REC.1403.090) (https://ethics.research.ac.ir/ProposalCertificateEn.php?id=479859&Print), Tabriz, Iran.

Keywords:  Parkinson disease; metabolomics analysis; neurodegeneration; pantothenic acid; vitamin B5

DOI:  https://doi.org/10.1093/nutrit/nuaf232
Nat Rev Drug Discov. 2026 Feb 16.

Therapeutic targeting of neuroimmune mechanisms in neurodegeneration.

Kathryn M Monroe, Soyon Hong, Joseph W Lewcock, Andrew C Yang.

Effective treatments for age-related chronic neurodegenerative diseases such as Alzheimer's disease remain limited, in part because the molecular drivers of cognitive decline are still not fully understood. Human genetic studies, together with detailed analysis of disease pathology, indicate that the immune system has an important influence on disease progression. Research to date has focused largely on microglia - specialized innate immune cells that reside within the central nervous system (CNS) - as functional studies combined with deep transcriptional profiling have improved our understanding of this innate immune cell type in neurodegeneration and have identified several potential therapeutic targets. Increasing evidence now shows that microglia coordinate diverse CNS and peripheral cell populations to shape disease outcomes. In this Review, we discuss these neuroimmune interactions, which reveal a more intricate framework for how the central and peripheral immune systems may influence neurodegeneration. These insights could redirect future drug discovery efforts towards immune targets that complement existing therapies aimed at core pathological features. We also outline how this knowledge suggests new therapeutic strategies and highlight a critical need for disease-specific neuroimmune biomarkers.

DOI: https://doi.org/10.1038/s41573-025-01370-7
Front Microbiol. 2026 ;17 1746359

Gut microbiota: new links between exercise and disease.

Yini Wu, Yinfeng Wang, Qingtong Zhang, Lijuan Yao, Zhennan Ma, Leqin Chen.

  As the "second genome" of the human body, the intestinal microbiota plays a key role in preventing the onset and progression of obesity, metabolic disorders, and inflammatory diseases by modulating immune function, maintaining metabolic homeostasis, and reinforcing mucosal barrier integrity. This review systematically investigates the biological and physiological mechanisms underlying the interaction between exercise and the gut microbiota in disease prevention. Existing evidence suggests that exercise, as a non-pharmacological intervention, can prevent and manage obesity, diabetes, and neurodegenerative diseases by reshaping the composition and function of the gut microbiota, suppressing oxidative stress, reducing inflammatory markers, and maintaining intestinal mucosal barrier homeostasis. Current evidence has begun to elucidate the molecular mechanisms by which the gut microbiota mediates disease prevention and progression under varying exercise intensities, modalities, and durations. However, the structural and functional changes of the gut microbiota induced by different exercise doses remain insufficiently characterized, limiting the ability to establish clear exercise-dose relationships for disease prevention. This article systematically reviews the fundamental characteristics of the gut microbiota and the physiological mechanisms underlying exercise intervention in disease prevention through the microbiota, with a focus on exploring the interaction network among the microbiota, exercise, and disease states. Although exercise-induced regulation of the gut microbiota and its metabolites, including short-chain fatty acids (SCFAs), tryptophan metabolites, and bile acids, has demonstrated adaptive and regulatory advantages in disease prevention, the specific effects of exercise-driven changes in the microbiota on various diseases still require extensive experimental validation. In the future, greater attention should be given to the differential effects of varying exercise doses on individual gut microbiota profiles, as well as the long-term impact of exercise-modulated gut microbiota on disease outcomes. On this basis, novel therapeutic strategies should be proposed to promote the enrichment of exercise-responsive microbial populations and harness the protective potential of the gut microbiota for disease prevention.

Keywords:  aerobic exercise; gut microbiota; immune diseases; metabolic diseases; moderate-intensity exercise; neurological diseases

DOI:  https://doi.org/10.3389/fmicb.2026.1746359
Int Immunopharmacol. 2026 Feb 13. pii: S1567-5769(26)00173-6. [Epub ahead of print]174 116329

The human and murine immune systems: regulated by dichotomous molecules.

Rafael Cardoso Maciel Costa Silva.

  In this review, the important and dichotomous role of several receptors, inflammatory mediators and cells in the fine-tuning of immune responses in humans and mice is discussed. The underappreciated dichotomy of at least some molecules of the immune system, like PD-1, Gasdermin D and several cytokines, leads to unpredictable outcomes, especially when these molecules are targeted or manipulated for the treatment of distinct diseases. In this sense, this manuscript aims to highlight that, under particular situations, macromolecules involved in proinflammatory responses might lead to anti-inflammatory effects and vice versa. Understanding the mechanisms involved in this dichotomy might lead to specific therapies under certain conditions and/or important new molecular targets for the treatment of many diseases, minimizing collateral effects. In conclusion, this manuscript underscores how the immune system is controlled by the fine balance between the dichotomous effects of single molecules, depending on the circumstances.

Keywords:  Checkpoint receptors; Immune system; Inflammatory responses; Resolution

DOI:  https://doi.org/10.1016/j.intimp.2026.116329
Neurobiol Dis. 2026 Feb 13. pii: S0969-9961(26)00064-1. [Epub ahead of print]221 107320

C9orf72-derived dipeptide repeat proteins poly-PR disrupt membrane excitability and synaptic function in cortical neurons.

Shao-Ming Wang, Jui-Cheng Chan, Engkarat Supapatarnun, Chao-Yi Tsai, Phan Thi Ngoc Lan, Eddie Feng-Ju Weng.

  Amyotrophic lateral sclerosis (ALS) is one of the most fatal neurodegenerative disease, with the most common genetic form of the ALS is associated with hexanucleotide GGGGCC repeat expansions in the first intron of C9orf72 gene. Cortical hyperexcitability is one of the symptoms reported in several forms of ALS and implicated as a cause of neuronal death, however, the underlying mechanisms are still unclear. The dipeptide repeat (DPR) proteins produced from hexanucleotide repeat expansion have been shown toxic to neurons and induce cellular damages. In this study, we explore relationships between the membrane excitability of cortical neurons and the expression of one of the DPR proteins poly-proline-arginine (poly-PR). We found that expression of poly-PR in primary cultured cortical neurons induced an elevation of intrinsic membrane excitability and decreases in dendritic arborization and excitatory synaptic activity. The increased membrane excitability can be restored by Nav channel inhibitor riluzole and Kv7 channel activator retigabine. Our results suggest a rescuable ion channel-mediated hyperexcitability induced by poly-PR expression in cortical neurons, providing a foundation for developing targeted therapies for C9orf72 ALS.

Keywords:  Amyotrophic lateral sclerosis; C9orf72; Hyperexcitability; Poly-PR

DOI:  https://doi.org/10.1016/j.nbd.2026.107320