bims-micgli 2025-09-21 papers

bims-micgli

Biomed News

on Microglia

Issue of 2025–09–21
25 papers selected by
Matheus Garcia Fragas, Universidade de São Paulo

Stress-Responsive Transcriptomic Signatures in Human iPSC-Derived Microglia Reveal Links to Alzheimer's Disease Risk Genes.
ACE1 does not influence cerebral Aβ degradation or amyloid plaque accumulation in 5XFAD mice.
C4d, a high-affinity LilrB2 ligand, is elevated in Alzheimer's disease and mediates synapse pruning.
APOE4 promotes cerebrovascular fibrosis and amyloid deposition via a pericyte-to-myofibroblast transition.
Plasma Phosphorylated Tau 217 to Identify Preclinical Alzheimer Disease.
Inhibition of autophagy-lysosomal function exacerbates microglial and monocyte lipid metabolism reprograming and dysfunction after brain injury.
Microglia and myeloperoxidase in neuroinflammatory and neurodegenerative diseases.
Aβ oligomers promote lipid droplet accumulation and inflammatory responses in astrocytes but not neurons.
Differences and overlaps in TDP-43 pathology of 'pure' LATE-NC compared to LATE-NC coexisting with Alzheimer's disease.
Multicolor fate mapping of microglia reveals polyclonal proliferation, heterogeneity, and cell-cell interactions after ischemic stroke in mice.
Clearing truncated tau protein restores neuronal function and prevents microglia activation in tauopathy mice.
Dynamic alterations of dural and bone marrow B cells in an animal model of progressive multiple sclerosis.
Ap1s1 reduction in the aging brain heightens neuronal vulnerability to amyloid-β and oxidative stress in Alzheimer's pathogenesis.
Extracellular Vesicles Released From Cortical Neurons Influence Spontaneous Activity of Recipient Neurons.
Beyond inflammation: a comprehensive microglial regulation model in chronic pain.
Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimer's disease brain.
Cortical tau deposition promotes atrophy in connected white matter regions in Alzheimer's disease.
Periventricular diffusivity reflects APOE ε4-modulated amyloid accumulation and cognitive impairment in the Alzheimer's disease continuum.
Altered Inflammatory Signature in a C9ORF72-ALS iPSC-Derived Motor Neuron and Microglia Coculture Model.
Tau, amyloid-beta and alpha-synuclein co-pathologies synergistically enhance neuroinflammation and neuropathology.
HIF-1α-induced microglia-mediated neuroinflammation is involved in Alzheimer's disease: Evidence from single-cell transcriptomic analysis.
Dysregulation of Neuronal Activity-Dependent Immediate Early Genes in a Mouse Model of Angelman Syndrome.
Limbic Alzheimer's co-pathology in multiple system atrophy is associated with cognitive impairment and diagnostic inaccuracy.
Role of ezrin-radixin-moesin proteins in the regulation of inflammatory cytokine expression in activated microglia.
Neuroinflammatory crosstalk between microglia and astrocytes increases viral replication in an iPSC-derived model of CNS HIV infection.

bioRxiv. 2025 Sep 03. pii: 2025.08.30.673269. [Epub ahead of print]

Stress-Responsive Transcriptomic Signatures in Human iPSC-Derived Microglia Reveal Links to Alzheimer's Disease Risk Genes.

Devin Saunders, Faraz Sultan, Ricardo A Vialle, Nicola A Kearns, Bernard Ng, Eric M Clark, Himanshu Vyas, Sashini De Tissera, Jishu Xu, David A Bennett, Yanling Wang.

Cellular stress responses are essential for maintaining homeostasis in the face of environmental or internal challenges. In the central nervous system, microglia serve as key stress sensors and immune responders, shaping neuroinflammatory processes and disease progression. However, the molecular programs engaged by distinct stressors and their impact on microglial viability remain incompletely understood. In this study, we used human induced pluripotent stem cell-derived microglia-like cells to investigate stress responses to amyloid beta (Aβ), a chronic Alzheimer's disease-related stressor, and lipopolysaccharide (LPS), a classical acute inflammatory stimulus. Using single-cell RNA sequencing, we mapped the transcriptional programs activated by each condition and benchmarked these states against reference microglial datasets from mouse and human brains. In parallel, we performed a pooled CRISPR interference screen targeting Alzheimer's disease-associated microglial genes to identify genetic determinants of microglial survival. We found that Aβ and LPS elicit partially overlapping but distinct transcriptional responses. Aβ induced more focused and disease-associated gene expression changes, while LPS triggered broad inflammatory activation and stronger cell death signatures. A subset of genes activated by stress overlapped with Alzheimer's disease risk genes and with hits from the survival screen, suggesting that disease-associated microglial genes may contribute to stress adaptation and cellular fitness. These results demonstrate that iPSC-derived microglia-like cells can recapitulate in vivo-like stress-responsive states and offer a tractable platform to investigate genetic and environmental influences on microglial behavior. Together, our findings reveal transcriptional programs that link stress sensing, survival regulation, and Alzheimer's disease-associated gene networks, providing a foundation for future efforts to enhance microglial resilience in neurodegenerative disease contexts.

DOI: https://doi.org/10.1101/2025.08.30.673269
PLoS One. 2025 ;20(9): e0330193

ACE1 does not influence cerebral Aβ degradation or amyloid plaque accumulation in 5XFAD mice.

Sohee Jeon, Alia O Alia, Jelena Popovic, Robert Vassar, Leah K Cuddy.

Alzheimer's disease is the most common form of dementia, and multiple lines of evidence support the relevance of Aβ deposition and amyloid plaque accumulation in the neurotoxicity and cognitive decline in AD. Rare mutations in angiotensin-converting-enzyme-1 have been highly associated with late onset AD patients; however, the mechanism for ACE1 mutation in AD pathogenesis is unknown. While numerous studies have shown that ACE1 indeed catabolizes Aβ, majority of these studies were performed in vitro, and conflicting results have been reported in clinical and in vivo systems. Therefore, we further investigated this in vivo by generating and examining a novel mouse model. Specifically, we analyzed 6-month-old 5XFAD mice with ACE1 knockdown restricted to excitatory neurons, achieved by driving Cre recombinase expression under the CamKIIα promoter. These mice were generated by crossing 5XFAD mice to ACE1 conditional knockout mice expressing Cre specifically in excitatory neurons. Our analyses revealed that neuronal ACE1 knockdown does not significantly affect amyloid plaque load and neuroinflammation in the hippocampus and cortex of 5XFAD mice at 6-months of age.

DOI: https://doi.org/10.1371/journal.pone.0330193
Proc Natl Acad Sci U S A. 2025 Sep 23. 122(38): e2519253122

C4d, a high-affinity LilrB2 ligand, is elevated in Alzheimer's disease and mediates synapse pruning.

Barbara K Brott, Aram J Raissi, Kristina D Micheva, Jost Vielmetter, Monique S Mendes, Caroline J Baccus, Jolie Huang, Carla J Shatz.

  Synapse pruning sculpts neural circuits throughout life. The human Leukocyte immunoglobulin-like receptor type B2 (LilrB2)/murine Paired immunoglobulin receptor B (PirB) receptors expressed in neurons and complement protein C4 have been separately implicated in pruning. Here, we report that C4d, a C4 cleavage product with unknown function, binds LilrB2/PirB with nanomolar affinity. C4d and LilrB2 colocalize at excitatory synapses in the human cerebral cortex as well as with beta amyloid in Alzheimer's disease (AD). C4d, as well as C4, increase with age and more so in AD. To examine whether C4d-PirB interactions can drive pruning, dendritic spines-the postsynaptic structure of excitatory synapses-were monitored on L5 pyramidal neurons in the mouse cerebral cortex: A significant decrease in dendritic spine density occurred in WT with C4d exposure, but KO of PirB completely prevented this loss. Together, our findings reveal an unexpected physiological role for C4d in pruning and imply that different complement cascade components may collaborate to engage both neuronal and glial-specific effectors of synaptic pruning.

Keywords:  Alzheimer’s disease; complement component C4d; human cerebral cortex; neuronal pruning receptors; synapse pruning

DOI:  https://doi.org/10.1073/pnas.2519253122
bioRxiv. 2025 Sep 09. pii: 2025.09.04.674192. [Epub ahead of print]

APOE4 promotes cerebrovascular fibrosis and amyloid deposition via a pericyte-to-myofibroblast transition.

Braxton R Schuldt, Dominic Haworth-Staines, Andrea Perez-Arevalo, Diede W M Broekaart, Leon Wang, Georgia Gallagher, Grace Rabinowitz, Alison M Goate, Towfique Raj, Ana C Pereira, Joel W Blanchard.

Cerebrovascular disease is a major but poorly understood feature of Alzheimer's disease (AD). The strongest genetic AD risk factor, APOE4, is associated with cerebrovascular degeneration, including vascular amyloid deposition and fibrosis. To uncover how APOE4 promotes cerebrovascular pathology, we generated a single-cell transcriptomic atlas of human brain vasculature. In APOE4 carriers, pericyte abundance was significantly reduced and accompanied by the emergence of a myofibroblast-like cell population co-expressing contraction and extracellular matrix genes. Immunostaining confirmed non-vascular myofibroblasts in APOE4 human and mouse brains. We show that APOE4 pericytes transition into myofibroblasts that secrete fibronectin, which promotes vascular amyloid accumulation. Computational and experimental analyses identified elevated TGF-β signaling as the driver of this pericyte-to-myofibroblast transition. Inhibition of TGF-β restored pericyte coverage and reduced vascular fibrosis and amyloid to APOE3 levels, revealing a targetable mechanism linking APOE4 to cerebrovascular pathology in AD.
Summary: Cerebrovascular disease is a prominent but poorly understood component of Alzheimer's disease (AD). The strongest genetic risk factor for AD, APOE4, is associated with multiple cerebrovascular pathologies, including vascular amyloid accumulation and fibrosis. APOE4 also renders the cerebrovasculature fragile to the point where the only disease-modifying AD therapeutic, anti-amyloid monoclonal antibodies, are warned against use in APOE4 carriers due to a high risk of hemorrhage and edema. To determine how APOE4 impacts cerebrovascular cells and pathogenesis, we generated a high-resolution single-cell transcriptomics atlas of human cerebrovasculature from APOE4 carriers and non-carriers. In APOE4 individuals, we found that the number of microvascular pericytes was significantly reduced. Notably, loss of pericytes in APOE4 carriers was accompanied by the emergence of a unique population of mural cells characterized by high expression of contraction and extracellular matrix (ECM) genes, hallmarks of myofibroblasts. Immunostaining revealed the presence of myofibroblasts surrounding the microvasculature in APOE4 human hippocampi that were absent in age-matched APOE3/3 controls, even in cases of AD. Myofibroblast presence coincided with a significant increase in fibronectin and amyloid surrounding the vasculature. Myofibroblasts were also present around the microvasculature of aged APOE4/4 but not APOE3/3 mice, suggesting myofibroblast appearance is a direct effect of the APOE4 genotype and not a technical artifact of processing human tissue. To determine the mechanisms and functional implications of APOE4-mediated myofibroblast, we leveraged a vascularized human brain tissue (miBrain) derived from induced pluripotent stem cells. Similar to the post-mortem human brain, APOE4/4 miBrains showed significantly reduced microvascular pericyte coverage, coinciding with the emergence of myofibroblasts co-expressing ECM and contractile genes. Lineage tracing and genetic mixing experiments confirmed that the myofibroblasts emerge from APOE4 pericytes and secrete fibronectin-rich ECM. Knocking down fibronectin in APOE4 mural cells significantly reduced vascular amyloid accumulation. To determine how myofibroblast-like cells arise in the APOE4 brain, we performed computational analysis (NicheNet) on our post-mortem human single-cell transcriptomics cerebrovascular atlas. This predicted that TGF-β is the top causal driver of the pericyte-to-myofibroblast transition. Consistent with this prediction, we found that TGF-β ligands in astrocytes and receptors in mural cells are significantly upregulated compared to APOE3 controls. Chemical and genetic inhibition of TGF-β signaling in APOE4 miBrains significantly reduced myofibroblast presence, while concurrently increasing pericyte microvascular coverage and ultimately lowering vascular fibrosis and amyloid accumulation to APOE3 levels. Using a comprehensive three-pronged approach incorporating analysis of human post-mortem brain, APOE humanized mice, and human iPSC-derived vascularized brain tissue, we demonstrate that APOE4 in mouse and human brain tissue causes increased TGF-β signaling, promoting a pericyte-to-myofibroblast transition that leads to vascular fibrosis and amyloid deposition. This provides critical insight into the mechanisms underlying APOE4 cerebrovascular dysfunction, highlighting new diagnostic and therapeutic strategies for a major AD risk population.

DOI: https://doi.org/10.1101/2025.09.04.674192
JAMA Neurol. 2025 Sep 15.

Plasma Phosphorylated Tau 217 to Identify Preclinical Alzheimer Disease.

ADNI, ALFA, and PREVENT-AD Study Groups

Importance: Advances in Alzheimer disease (AD) have shifted research focus to earlier disease stages, necessitating more scalable approaches to identify cognitively unimpaired individuals with amyloid β (Aβ) pathology.
Objective: To assess the utility of plasma phosphorylated tau 217 (p-tau217) for classifying Aβ status in cognitively unimpaired individuals, both as a stand-alone test and in a 2-step approach where positive plasma results were confirmed using a second modality (Aβ positron emission tomography [PET] or cerebrospinal fluid [CSF]).
Design, Setting, and Participants: This cross-sectional cohort study used data collected between June 2009 and March 2024. We included 2916 cognitively unimpaired participants from 12 international independent observational cohorts in the US, Europe, Australia, and Canada with available plasma p-tau217 levels and CSF or PET Aβ biomarkers. Performance comparisons between mass spectrometry and immunoassay-based p-tau217 measurements were also performed (n = 964).
Exposures: Plasma p-tau217 levels measured by immunoassay.
Main Outcome and Measures: Aβ status, determined by CSF or Aβ PET biomarkers.
Results: Participants had a mean (SD) age of 66.9 (9.9) years; 971 (33.3%) were Aβ positive by either CSF or PET, 1667 (57.2%) were women, and 1108 (38.1%) carried at least 1 APOE ε4 allele. As a stand-alone test, plasma p-tau217 achieved a positive predictive value (PPV) of 79% (95% CI, 74-84) and an overall accuracy of 81% (95% CI, 80-82). In a 2-step workflow, the PPV and accuracy significantly increased to 91% (95% CI, 86-95). While this approach required screening of 677 individuals with plasma p-tau217 to identify 100 Aβ-positive individuals, compared to 536 participants when using PET alone, it reduced the need for PET testing to 124. Immunoassays demonstrated comparable PPVs to mass spectrometry (80% [95% CI, 74-86] vs 85% [95% CI, 81-90]; P = .12) but significantly lower overall accuracy (82% [95% CI, 79-84]% vs 88 [95% CI, 86-90]; P < .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P < .001).
Conclusions and Relevance: The findings highlight the potential of plasma p-tau217 as a stand-alone test-or when used in a sequential 2-step approach alongside PET or CSF testing-as a cost-effective, scalable, and minimally burdensome strategy for identifying preclinical AD. Tailored screening workflows that incorporate p-tau217 can improve efficiency in participant selection for preclinical AD trials and, in the future, help guide access to disease-modifying treatments.

DOI: https://doi.org/10.1001/jamaneurol.2025.3217
bioRxiv. 2025 Sep 08. pii: 2025.09.04.674092. [Epub ahead of print]

Inhibition of autophagy-lysosomal function exacerbates microglial and monocyte lipid metabolism reprograming and dysfunction after brain injury.

Amir A Mehrabani-Tabari, Nivedita Hegdekar, Brian R Herb, Sazia Arefin Kachi, Chinmoy Sarkar, Sagarina Thapa, Dexter Ph Nguyen, Yulemni Morel, Mehari M Weldemariam, Ludovic Muller, W Temple Andrews, Marcia Cortes-Gutierrez, Xiaoxuan Fan, Natarajan Ayithan, Olivia Pettyjohn-Robin, Sabrina Bustos, Lacey K Greer, Jessica T Gore, Maureen A Kane, Seth A Ament, Jace W Jones, Marta M Lipinski.

CNS has an overall higher level of lipids than all tissues except adipose and contains up to 25% of total body cholesterol. Recent data demonstrate a complex crosstalk between lipid metabolism and inflammation, suggesting potential contribution of the lipid-rich brain environment to neuroinflammation. While recent data support the importance of brain lipid environment to inflammatory changes observed in age related chronic neurodegenerative diseases, in vivo interactions between lipid environment, lipid metabolism and neuroinflammation in acute brain disease and injury remain poorly understood. Here we utilize a mouse model of traumatic brain injury (TBI) to demonstrate that acute neurotrauma leads to widespread lipid metabolism reprograming in all microglial and brain associated and infiltrating monocyte populations. Additionally, we identify unique microglial and monocyte populations with higher degree of lipid metabolism reprograming and pronounced accumulation of neutral storage lipids, including cholesteryl esters and triglycerides. These lipids accumulate not only in lipid droplets but also in the microglial and monocyte lysosomes and are associated with lysosomal dysfunction and inhibition of autophagy after TBI. Our data indicate that lipid accumulation in these cells is the result of altered lipid handling rather than lipid synthesis and is triggered by phagocytosis of lipid-rich myelin debris generated after TBI. Finally, we use mice with autophagy defects in microglia and monocytes to demonstrate that further inhibition of autophagy leads to more pronounced lipid metabolism reprograming and exacerbated cellular lipid accumulation. Our data suggest a pathological feedback loop, where lipid phagocytosis causes inhibition of autophagy-lysosomal function, which in turn exacerbates cellular lipid retention, reprograming and inflammation.

DOI: https://doi.org/10.1101/2025.09.04.674092
Curr Opin Immunol. 2025 Sep 17. pii: S0952-7915(25)00136-0. [Epub ahead of print]97 102660

Microglia and myeloperoxidase in neuroinflammatory and neurodegenerative diseases.

Lorenzo Del Moro, Enrico Brunetta, M Eric Gershwin, Carlo Selmi.

The dogma of an impenetrable blood-brain barrier (BBB) has given way to the view that resident immune cells within the central nervous system respond to a variety of blood-borne soluble factors, particularly cytokines, and play an important functional role. In particular, microglia cells contribute to the regulation of neuroinflammation, with both protective and pathological roles. Specific microglia activation states variably influence the progression of neuroinflammatory and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Significant evidence indicates that gut microbiota-derived products regulate microglial function across the lifespan and influence the BBB. Myeloperoxidase (MPO) catalyzes the conversion of hydrogen peroxide and chloride ions into hypochlorous acid, a potent oxidant implicated in oxidative tissue damage and modulation of inflammatory signaling. Elevated MPO levels in the central nervous system have been correlated with human disease and the dysregulation of MPO activity in microglia is particularly detrimental, as it amplifies the oxidative stress, disrupts the BBB integrity, and potentiates the neuroinflammatory cascades through the activation of transcription factors like NF-κB. Targeting MPO activity through selective inhibitors or antioxidant strategies may attenuate microglial activation and reduce neuroinflammation, highlighting its potential as a therapeutic target, but the regulatory mechanisms governing MPO expression in microglia and its interplay with other inflammatory mediators remain poorly understood. New research efforts into the relationship between gut microbiota, microglia, MPO, and neuroinflammation are essential to unravel the complexities of neuropathology in a variety of conditions beyond neurodegenerative diseases.

DOI: https://doi.org/10.1016/j.coi.2025.102660
Brain Res Bull. 2025 Sep 17. pii: S0361-9230(25)00368-5. [Epub ahead of print] 111556

Aβ oligomers promote lipid droplet accumulation and inflammatory responses in astrocytes but not neurons.

Hui Zhang, Yazhen Huang, Wei Wang.

  Lipid droplets (LDs) are dynamic organelles central to cellular lipid homeostasis. Emerging evidence implicates LDs in Alzheimer's disease (AD) pathogenesis, though their cell-type-specific roles remain poorly defined. Here, we investigated the effects of amyloid-beta oligomers (AβOs) on LDs accumulation, oxidative stress, and inflammatory activation in primary astrocytes and neurons. We found that AβOs selectively triggered robust LDs formation in astrocytes, accompanied by significant increases in triglyceride (TG) and cholesterol (TC) content, and upregulation of the LD-associated protein perilipin 2 (PLIN2). Furthermore, AβOs induced pronounced oxidative stress, evidenced by elevated Malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), and promoted inflammatory activation via increased secretion of tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) in astrocytes. By contrast, neurons showed no significant changes in lipid metabolism, oxidative stress, or inflammatory responses under identical treatment conditions. Our results underscore the central role of astrocytes in AβO-induced metabolic and inflammatory dysregulation, revealing a cell-type-specific vulnerability with potential implications for AD pathogenesis. These in vitro findings provide a mechanistic basis for lipid-focused therapeutic strategies, pending further in vivo validation.

Keywords:  Alzheimer's disease; astrocyte; inflammation; lipid droplets; oxidative stress; perilipin2

DOI:  https://doi.org/10.1016/j.brainresbull.2025.111556
Acta Neuropathol. 2025 Sep 15. 150(1): 28

Differences and overlaps in TDP-43 pathology of 'pure' LATE-NC compared to LATE-NC coexisting with Alzheimer's disease.

Sandra O Tomé, Klara Gawor, Simona Ospitalieri, Alicja Ronisz, Markus Otto, Christine A F von Arnim, Estifanos Ghebremedhin, Celeste Laureyssen, Kristel Sleegers, Rik Vandenberghe, Peter T Nelson, Dietmar Rudolf Thal.

  Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a common substrate of dementia in the elderly. LATE and Alzheimer's disease (AD) share similar clinical features, and their underlying neuropathological changes-LATE-NC and ADNC-commonly co-occur. However, the histomorphological and molecular features of TDP-43 pathology in LATE-NC with or without coexisting ADNC are not yet well understood. We performed immunohistochemistry in paraffin-embedded tissue from the hippocampus, amygdala, and temporal and frontal cortices of 108 human autopsy cases including 20 cognitively unimpaired controls, 20 AD dementia cases with moderate-high severity of ADNC without LATE-NC (ADNC group), 34 AD dementia cases with LATE-NC (ADNC + LATE-NC group), 17 dementia cases with LATE-NC but no/low ADNC (pure LATE-NC group), and 17 FTLD-TDP Type A cases. We assessed TDP-43 aggregate morphology and composition using antibodies against different TDP-43 epitopes: pS409/410, pS403/pS404, and C- and N-terminal TDP-43. We also investigated nuclear clearance of physiological TDP-43 and cytoplasmic colocalization of TDP-43 and tau proteins. Pure LATE-NC cases were on average 10 years older at death than ADNC + LATE-NC, had less cognitive impairment, higher prevalence of argyrophilic grain disease (AGD) pathology, aging-related tau astrogliopathy (ARTAG), and APOEε2 allele. They also tended to show lower APOEε4 frequencies, but similar frequencies of hippocampal sclerosis and LATE-NC stages. Importantly, LATE-NC predominantly displayed a mesh-like neuritic TDP-43 pattern in the hippocampus, extending from CA1/2 to subiculum. This mesh-like pattern was present in 81% of pure LATE-NC cases and only in 18% of ADNC + LATE-NC. This pattern was also observed in 53% of FTLD-TDP Type A cases. Moreover, the aggregate composition differed in pure LATE-NC and ADNC + LATE-NC, with LATE-NC cases exhibiting increased burdens of several phosphorylated and non-phosphorylated TDP-43 species, while only the pS409/pS410 epitope was significantly associated with ADNC + LATE-NC in the amygdala. Nuclear clearance patterns also tended to differ between pure LATE-NC and ADNC + LATE-NC. Similar to ADNC + LATE-NC, TDP-43 and tau proteinopathies colocalized in pure LATE-NC with comorbid primary age-related tauopathy (PART) or low ADNC. These data suggest that LATE-NC tends to be modified in the presence of moderate-high ADNC. These differences may reflect upstream influences (age, genetics, and environmental risk factors), direct protein-protein interactions, and/or other impacts of ADNC-related mechanisms on TDP-43 proteinopathy, potentially relevant for clinical trial design and future therapeutic applications.

Keywords:  Alzheimer’s disease; LATE-NC; Limbic-predominant age-related TDP-43 encephalopathy; Neuropathology

DOI:  https://doi.org/10.1007/s00401-025-02929-9
Nat Commun. 2025 Sep 16. 16(1): 8294

Multicolor fate mapping of microglia reveals polyclonal proliferation, heterogeneity, and cell-cell interactions after ischemic stroke in mice.

Majed Kikhia, Simone Schilling, Marie-Louise Herzog, Michelle Livne, Marcus Semtner, Tuan Leng Tay, Marco Prinz, Helmut Kettenmann, Matthias Endres, Golo Kronenberg, Ria Göttert, Karen Gertz.

Microglial proliferation is a principal element of the inflammatory response to brain ischemia. However, the precise proliferation dynamics, phenotype acquisition, and functional consequences of newly emerging microglia are not yet understood. Using multicolor fate mapping and computational methods, we here demonstrate that microglia exhibit polyclonal proliferation in the ischemic lesion of female mice. The peak number of clones occurs at 14 days, while the largest clones are observed at 4 weeks post-stroke. Whole-cell patch-clamp recordings of microglia reveal a homogeneous acute response to ischemia with a pattern of outward and inward currents that evolves over time. In the resolution phase, 8 weeks post-stroke, microglial cells within one clone share similar membrane properties, while neighboring microglia from different clones display more heterogeneous electrophysiological profiles. Super-resolution microscopy and live-cell imaging unmask various forms of cell-cell interactions between microglial cells from different clones. Overall, this study demonstrates the polyclonal proliferation of microglia after cerebral ischemia and suggests that clonality contributes to their functional heterogeneity. Thus, targeting clones with specific functional phenotypes may have potential for future therapeutic modulation of microglia after stroke.

DOI: https://doi.org/10.1038/s41467-025-63949-3
Cell Rep. 2025 Sep 16. pii: S2211-1247(25)01062-9. [Epub ahead of print]44(10): 116291

Clearing truncated tau protein restores neuronal function and prevents microglia activation in tauopathy mice.

Alejandro Martín-Ávila, Swananda R Modak, Hameetha B Rajamohamedsait, Andie Dodge, Dov B Shamir, Senthilkumar Krishnaswamy, Leslie A Sandusky-Beltran, Marilyn Walker, Yan Lin, Erin E Congdon, Einar M Sigurdsson.

  Tau protein truncated at Asp 421 is a characteristic feature of Alzheimer's disease and other tauopathies. Here, we show that a monoclonal antibody against Asp421, 5G2, cleared insoluble tau in the brains of JNPL3 mice, decreased tau levels in brain interstitial fluid in awake JNPL3 mice, improved in vivo neuronal function, and reduced microglial Iba-1 expression in PS19 mice, in which neuronal tau aggregation and dysfunction occurred earlier than microglial activation. For mechanistic insight using culture models, 5G2 prevented tau-mediated toxicity, cleared extra- and intracellular tau, and prevented microgliosis. TRIM21 knockdown reduced neuronal retention of tau antibodies and their acute but not longer-term efficacy. Inhibition of the endosomal/lysosomal pathway but not the proteasomal pathway blocked 5G2-mediated neuroprotection and tau clearance. These findings support targeting the Asp421 truncated tau protein to treat tauopathies, indicate that tau-associated neuronal dysfunction precedes microglial activation, and that intraneuronal antibody-mediated tau clearance is mostly via the lysosomes.

Keywords:  Asp421 antibody; CP: Cell biology; CP: Neuroscience; TRIM21; calcium imaging; in vivo; microglia; neurons; tauopathy; truncated tau

DOI:  https://doi.org/10.1016/j.celrep.2025.116291
J Exp Med. 2025 Dec 01. pii: e20241255. [Epub ahead of print]222(12):

Dynamic alterations of dural and bone marrow B cells in an animal model of progressive multiple sclerosis.

Alexandra Florescu, Michelle Zuo, Angela A Wang, Kevin Champagne-Jorgensen, Mohammed A Noor, Lesley A Ward, Erwin van Puijenbroek, Christian Klein, Jennifer L Gommerman.

In multiple sclerosis (MS), the leptomeninges (LM) are populated with immune cell aggregates that correlate with disease progression. The impact of LM inflammation on the adjacent dura is largely unknown. Using a mouse model of MS that induces brain LM inflammation and age-dependent disease progression, we found that encephalitogenic T cells and B220high B cells accumulate substantially in the brain LM and parenchyma of both young and aged mice, while the adjacent dura remains relatively inert. We also observed a population of anti-CD20-resistant B220low B cells in the dura and bone marrow that virtually disappear at disease onset and accumulate in the brain of young mice concomitant with disease remission. In contrast, aged mice show a paucity of brain-resident B220low B cells at the expense of class-switched B220high B cells accompanied by severe, chronic disease. In summary, dynamic changes in the brain, LM, and dural B cells are associated with age-dependent disease severity in an animal model of progressive MS.

DOI: https://doi.org/10.1084/jem.20241255
Alzheimers Res Ther. 2025 Sep 15. 17(1): 203

Ap1s1 reduction in the aging brain heightens neuronal vulnerability to amyloid-β and oxidative stress in Alzheimer's pathogenesis.

Xuehan Yang, Xinru Geng, Zhuoyan Xu, Yang Xu, Hao Han, Qiang Zhang, Honglian Jin, Yuxin Wang, Bin Sun, Ming Zhang, Siwei Zhang, Li Chen.

  Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is characterized by cognitive decline and memory impairment. Brain aging is indisputably the most significant risk factor for AD. Given that aging is a fundamental driving force behind the onset of AD, identifying the aging - regulated genes that contribute to AD development is of utmost importance. Such genes might hold the key to preventing AD or delaying the transition from normal aging to the disease state. In the present study, a comprehensive bioinformatic analysis was conducted on brain transcriptomic datasets obtained from both aging individuals and those with Alzheimer's disease. Among the shared differentially expressed genes, eight genes were found to be downregulated in both aging and AD datasets. Notably, reduced expression of adaptor protein complex 1 sigma 1 subunit (Ap1s1) was validated across multiple mouse models with varying degree of dementia, including aged mice, senescence-accelerated SAMP8 mice, 5xFAD amyloidosis mice, as well as cellular models, including senescent Neuro-2a (N2a) cells, and Aβ-treated or expressing N2a neurons. Functional studies revealed that Ap1s1 knockdown induced cellular senescence without directly impairing viability. However, Ap1s1 silencing exacerbated neuronal vulnerability to oxidative stress (H₂O₂) and Aβ toxicity, manifesting as Golgi-dispersion and reduced survival. Proteomic profiling following Ap1s1 depletion implicated dysregulation of rRNA modifications in the nucleus and cytosol, Golgi-associated vesicle biogenesis. These findings position Ap1s1 as a critical aging-related gene at the nexus of brain aging and AD pathogenesis, whose decline may predispose neurons to Alzheimer's-related insults. As such, Ap1s1 may represent a potential therapeutic target for mitigating aging-related cognitive decline and delaying the onset of AD.

Keywords:   Ap1s1 ; Aging; Alzheimer’s disease; Cellular senescence; Golgi dispersion; Neuronal vulnerability

DOI:  https://doi.org/10.1186/s13195-025-01861-0
J Neurochem. 2025 Sep;169(9): e70231

Extracellular Vesicles Released From Cortical Neurons Influence Spontaneous Activity of Recipient Neurons.

Franco Luis Lombino, Mohsin Shafiq, Andreu Matamoros-Angles, Jürgen R Schwarz, Kira V Gromova, Daniele Stajano, Bente Siebels, Leonie Bergmann, Tim Magnus, Michaela Schweizer, Franz Lennard Ricklefs, Hartmut Schlüter, Andrew F Hill, Matthias Kneussel, Markus Glatzel.

  Extracellular vesicles (EVs) are membranous structures that cells release into the extracellular space. EVs carry various molecules such as proteins, lipids, and nucleic acids, and serve as specialized transporters to influence other cells. In the central nervous system, EVs have been linked to many important processes, including intercellular communication, but molecular details of their physiological functions are not fully understood. Our study aimed to investigate how EVs are released by neuronal cells, and how they affect the neuronal activity of other recipient neurons. We show that mature primary cortical neurons release EVs from both their soma and dendrites. EVs released from neurons closely resemble non-neuronal EVs regarding size and marker proteins, and proteomic analyses showed that neuronally released EVs contain proteins typically acting in pre- and post-synaptic compartments. Interestingly, our analysis revealed that EVs alter spontaneous activity in target neurons by increasing the amplitude of postsynaptic potentials. In summary, our findings elaborate on the role of EVs in synaptic activity modulation in neurons mediated by glutamate receptors.

Keywords:  NMDA receptor; cortex; extracellular vesicles; hippocampus; synaptic activity

DOI:  https://doi.org/10.1111/jnc.70231
Mol Biol Rep. 2025 Sep 11. 52(1): 891

Beyond inflammation: a comprehensive microglial regulation model in chronic pain.

Yu Lei, Qian Wang, Feixiang Wang, Guo Mu.

  Chronic pain has emerged as a disorder of persistent neuroimmune dysregulation, with microglia playing a pivotal role in shaping maladaptive plasticity. Beyond classical inflammatory pathways, recent discoveries highlight microglial involvement in epigenetic remodeling, metabolic reprogramming, and synaptic modulation. These multidimensional processes sustain microglial activation and promote central sensitization, even in the absence of ongoing peripheral injury. This review proposes a comprehensive framework for understanding microglial regulation in chronic pain, emphasizing the failure of immune tolerance, aberrant neuron-glia signaling, and the emergence of disease-perpetuating microglial states. We further discuss therapeutic strategies aimed at selectively targeting microglial phenotypes, including HDAC inhibitors, metabolic modulators, and pathway-specific antagonists. By integrating mechanistic depth with translational insights, this review reframes microglia not only as inflammatory mediators, but as dynamic regulators whose dysregulation underlies pain chronification.

Keywords:  Chronic pain; Epigenetics; Metabolism; Microglia; Neuroimmune regulation

DOI:  https://doi.org/10.1007/s11033-025-11019-8
bioRxiv. 2025 Sep 09. pii: 2025.09.08.674963. [Epub ahead of print]

Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimer's disease brain.

Lauren N Carnevale, Piu Banerjee, Xu Zhang, Jazmin Navarro, Charlene K Raspur, Parth Patel, Tomohiro Nakamura, Emily Schahrer, Henry Scott, Nhi Lang, Jolene K Diedrich, Amanda J Roberts, John R Yates, Stuart A Lipton.

The mechanism(s) whereby redox stress mediates aberrant immune signaling in age-related neurological disorders remains largely unknown. Normally, the innate immune system mounts a robust response to infectious stimuli. However, unintentional activation by host-derived factors, such as aggregated proteins associated with neurodegenerative disorders or by cytoplasmic genomic or mitochondrial DNA, can elicit aberrant immune responses. One such immune response is represented by the cytosolic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Using redox chemical biology and mass spectrometry approaches, we identified S -nitrosylation of STING cysteine 148 as a novel posttranslational redox modification underlying aberrant type 1 interferon signaling in Alzheimer's disease (AD). Critically, we observed S -nitrosylated STING (SNO-STING) in postmortem human AD brains, in hiPSC-derived microglia (hiMG) exposed to amyloid-β (Aβ)/α-synuclein (αSyn) aggregates, and in 5xFAD transgenic mice. Mechanistically, our findings reveal that STING S -nitrosylation is critical in initiating signaling cascades by promoting the formation of disulfide-bonded STING oligomers. This leads to neuroinflammation early in the course of disease in vivo in 5xFAD mice with consequent synaptic loss. Collectively, our research supports the role of SNO-STING in neuroinflammation associated with AD, and points to a novel druggable cysteine residue in STING to prevent this S -nitrosylation reaction with its inherent inflammatory response.
One Sentence Summary: S -Nitrosylation of STING triggers activation of cGAS-STING signaling in Alzheimer's disease brain and subserves a novel link between excessive nitrosative stress and dysregulated innate immunity, thus contributing to disease progression.

DOI: https://doi.org/10.1101/2025.09.08.674963
Brain. 2025 Sep 12. pii: awaf339. [Epub ahead of print]

Cortical tau deposition promotes atrophy in connected white matter regions in Alzheimer's disease.

Julia Pescoller, Anna Dewenter, Amir Dehsarvi, Anna Steward, Lukas Frontzkowski, Zeyu Zhu, Sebastian N Roemer-Cassiano, Carla Palleis, Fabian Hirsch, Fabian Wagner, Hannah de Bruin, Boris Rauchmann, Robert Perneczky, Johannes Gnörich, Maura Malpetti, Rik Ossenkoppele, Michael Schöll, Johannes Levin, Günter Höglinger, Matthias Brendel, Nicolai Franzmeier.

  In Alzheimer's disease (AD), fibrillar tau pathology is a key driver of neurodegeneration and cortical atrophy. Yet, emerging evidence suggests that tau aggregates also contribute to white matter (WM) damage. Specifically, physiological tau stabilizes intra-axonal microtubules, while hyperphosphorylated tau disrupts microtubule integrity, ensuing intraneuronal tau aggregation, neuronal disconnection, and axonal degeneration. Therefore, we investigated whether cortical tau promotes atrophy in connected WM regions in AD. To this end, we included 186 amyloid-positive (Aβ+) patients across the AD spectrum and 102 cognitively normal (CN) amyloid-negative (Aβ-) participants from ADNI, with baseline amyloid-PET, tau-PET, and T1-weighted MRI. Longitudinal tau-PET and MRI (∼2-years) were available for a subset of 138 participants, to further assess the relationship between tau accumulation and WM atrophy over time. For replication, we included 378/60 CN Aβ+/Aβ- participants from the A4/LEARN cohort with baseline amyloid-PET, tau-PET, and T1-weighted MRI, where a subset of 141/4 CN Aβ+/Aβ- subjects had ∼5-year longitudinal tau-PET and MRI. Cortical tau-PET Standardized Uptake Value Ratios were extracted from 210 cortical regions of the Brainnetome Atlas. In addition, we used a diffusion MRI-based tractography template to determine WM volumes of fiber tracts connected to cortical regions using segmented T1-weighted MRI. Using linear regression, we tested whether higher cortical tau-PET at baseline was associated with (i) lower baseline WM volume and (ii) faster WM volume loss over time, and (iii) whether faster longitudinal tau-PET increases paralleled faster WM loss. Testing the reverse model examined whether baseline WM atrophy predicted faster subsequent tau-PET increase in connected regions. Models were adjusted for age, sex, intracranial volume, WM hyperintensity volume, ApoE4 status and global amyloid-PET. In ADNI, elevated baseline cortical tau-PET in temporal regions was associated with lower baseline WM volume in adjacent regions, with more pronounced effects in patients across the AD spectrum and with weaker associations in the preclinical A4/LEARN sample. In both samples, higher baseline temporo-parietal tau-PET as well as faster tau-PET increase over time were significantly linked to accelerated volume loss in connected WM regions, which was especially pronounced in individuals on the AD spectrum. Importantly, baseline WM volume did not predict subsequent tau-PET change rates in adjacent cortical regions, suggesting a unidirectional relationship between fibrillar tau and subsequent WM degeneration. Together, our findings suggest that cortical tau accumulation promotes atrophy in adjacent WM regions in AD, highlighting that tau-induced axonal degeneration and potentially neuronal disconnection may play a pivotal role in disease progression.

Keywords:  Alzheimer’s disease; neuroimaging; progressive white matter degeneration; tau pathology

DOI:  https://doi.org/10.1093/brain/awaf339
Alzheimers Dement. 2025 Sep;21(9): e70659

Periventricular diffusivity reflects APOE ε4-modulated amyloid accumulation and cognitive impairment in the Alzheimer's disease continuum.

Mayo Clinic Study of Aging

   INTRODUCTION: Altered glymphatic-related fluid dynamics are increasingly recognized as a feature of Alzheimer's disease (AD). We generalized an established diffusion imaging framework to quantify periventricular diffusivity (PVeD), hypothesizing that fast diffusion signals in the periventricular region can reflect amyloid beta (Aβ) deposition across the AD continuum.
METHODS: Participants from two multi-site cohorts (n = 440 and 414), comprising cognitively unimpaired individuals, those with mild cognitive impairment, and patients with AD, were included. We tested and validated the association of PVeD with Aβ burden and core AD characteristics.
RESULTS: Lower PVeD was extensively associated with greater Aβ burden, neurodegeneration, cognitive impairment, and clinical severity in the clinical cohort. Importantly, the relationship between PVeD and Aβ burden was significantly modulated by apolipoprotein E (APOE) ε4 status; APOE ε4 carriers exhibited a replicable stronger negative association. Baseline PVeD also predicted longitudinal cognitive decline.
DISCUSSION: These findings suggest that periventricular diffusion signals reflect APOE ε4-modulated Aβ burden and cognitive decline in AD.
HIGHLIGHTS: An automated method for quantifying periventricular diffusivity (PVeD) is developed. Lower PVeD is associated with higher amyloid load only in a mild cognitive impairment-dominant cohort. Higher amyloid burden may mediate the link between lower PVeD and poorer cognitive outcomes in the clinical cohort. Apolipoprotein E ε4 carriers show a reproducibly stronger inverse PVeD-amyloid association than non-carriers. Baseline PVeD can predict longitudinal Mini-Mental State Examination decline in two independent cohorts.

Keywords:  Alzheimer's disease; amyloid imaging; apolipoprotein E ε4; cognitive decline; dementia; diffusion tensor image analysis along the perivascular space; diffusion tensor imaging; diffusivity; perivascular space; periventricular area

DOI:  https://doi.org/10.1002/alz.70659
Glia. 2025 Sep 15.

Altered Inflammatory Signature in a C9ORF72-ALS iPSC-Derived Motor Neuron and Microglia Coculture Model.

Yujing Gao, Jessica L Brothwood, Harpreet Saini, Gregory A O'Sullivan, Carla F Bento, James M McCarthy, Nicola G Wallis, Elena Di Daniel, Brent Graham, Daniel M Tams.

  Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder involving multiple cell types in the central nervous system. The key pathological features of ALS include the degeneration of motor neurons and the initiation and propagation of neuroinflammation mediated by nonneuronal cell types such as microglia. Currently, the specific mechanisms underlying the involvement of microglia in neuroinflammation in ALS are unclear. Consequently, we generated several human-induced pluripotent stem cell (iPSC) derived motor neuron and microglia cocultures. We utilized ALS patient-derived iPSCs carrying a common genetic variant, the hexanucleotide repeat expansion (HRE) in C9ORF72, as well as C9ORF72 knockout (KO) iPSC lines. iPSC-derived motor neurons and microglia demonstrated expression of cell type-specific markers and were functional. Phenotypic assessments on motor neurons and microglia in mono- and cocultures identified dysfunction in the expression and secretion of inflammatory cytokines and chemokines in lipopolysaccharide (LPS)-stimulated C9ORF72 HRE and C9ORF72 KO microglia. Analysis of single-cell RNA sequencing data from microglia and motor neuron cocultures revealed cell type-specific transcriptomic changes. Specifically, we detected the removal of an LPS-responsive microglia subpopulation, correlating with a dampened inflammatory response in C9ORF72 HRE and C9ORF72 KO microglia. Overall, our results support the critical role of microglia-mediated neuroinflammation in ALS pathology, and our iPSC-derived models should prove a valuable platform for further mechanistic studies of ALS-associated pathways.

Keywords:  ALS; coculture; iPSCs; microglia; motor neuron; neuroinflammation; single‐cell RNA sequencing

DOI:  https://doi.org/10.1002/glia.70084
bioRxiv. 2025 Sep 04. pii: 2024.10.13.618101. [Epub ahead of print]

Tau, amyloid-beta and alpha-synuclein co-pathologies synergistically enhance neuroinflammation and neuropathology.

Jhodi M Webster, Ya-Ting Yang, Aidan T Miller, Asta Zane, Kasandra Scholz, William J Stone, Nikhita Mudium, Nicole J Corbin-Stein, Woong-Jai Won, Anna C Stoll, Kelsey M Greathouse, Noelle H Cooper, Lillian F Long, Phaedra N Manuel, Jeremy H Herskowitz, Talene A Yacoubian, Daniel J Tyrrell, Ivette M Sandoval, Fredric P Manfredsson, Jeffrey H Kordower, Ashley S Harms.

  Alzheimer's and Parkinson disease pathology often co-occur, with amyloid-β and phosphorylated tau, found in 30-50% of idiopathic Parkinson disease cases. α -synuclein inclusions, a hallmark of Parkinson disease, are present in 50% of Alzheimer's cases and the co-expression of these pathologies is linked to faster cognitive decline and earlier death. Immune activation is a hallmark of both diseases, but current model systems primarily examine each pathology in isolation. As such, how these co-pathologies interact to drive inflammation and neuronal loss remain poorly understood. To address this, we developed a co-pathology mouse model combining tau, amyloid-β, and α-synuclein. Here, we show that co-pathologies synergistically trigger a distinct and amplified neuroimmune response, marked by robust expansion of CD4+ and CD8+ tissue-resident memory T cells and increased CD68+ microglia, a population of activated, phagocytosing microglia, compared to single pathology brains. These changes were abundant in the hippocampus and cortex, regions showing elevated amyloid-β protein pathology load and enhanced neuronal loss with co-pathology expression. Our findings demonstrate that co-pathologies act synergistically to enhance immune activation prior to neurodegeneration. This model provides a platform for assessing mixed-pathology mechanisms and identifies key immune cell populations that may drive disease acceleration across Alzheimer's, Parkinson disease and their related dementias.

Keywords:  T cells; amyloid beta; co-pathologies; microglia; neuroinflammation; tau; α-synuclein

DOI:  https://doi.org/10.1101/2024.10.13.618101
J Alzheimers Dis. 2025 Sep 19. 13872877251378007

HIF-1α-induced microglia-mediated neuroinflammation is involved in Alzheimer's disease: Evidence from single-cell transcriptomic analysis.

Manyu Dong, Yilun Qian, Yao Geng, Ruiyu Wang, Yu Wang, Jili Cai, Xihui Wang, Ying Huang, Yan Liu, Wentao Liu, Qi Wu, Ying Shen.

  BackgroundMicroglia are central mediators of neuroinflammation in Alzheimer's disease (AD), contributing significantly to disease pathogenesis. Understanding microglial heterogeneity and their regulatory mechanisms is critical for identifying potential therapeutic targets.ObjectiveThis study aimed to investigate the diversity of microglial subpopulations in AD and uncover key transcriptional regulators driving their pathogenic activity.MethodsWe integrated bulk RNA sequencing data from AD patients and 5×FAD mouse models with single-cell RNA sequencing (scRNA-seq) to profile microglial heterogeneity. Differential gene expression, pathway enrichment, pseudotime trajectory, and SCENIC analyses were used to identify functionally distinct subsets and regulatory networks. Experimental validation was conducted through in vivo assays in 5×FAD mice and in vitro inhibition studies targeting HIF-1α.ResultsA unique microglial subpopulation, termed microglia_2, was identified with an inflammatory-angiogenic transcriptional signature that was enriched during AD progression. This subset showed significant activation of inflammatory pathways. Pseudotime and SCENIC analyses revealed HIF-1α as a master regulator of microglia_2. In 5×FAD mice, cognitive decline was accompanied by increased expression of HIF-1α and Apoe, as well as microglial activation in the prefrontal cortex. In vitro inhibition of HIF-1α significantly reduced microglial inflammation.ConclusionsOur study demonstrates that a specific microglial subpopulation characterized by elevated HIF-1α expression may contribute to AD-associated neuroinflammation. By integrating transcriptomic analyses and experimental validation, we provide cell type-specific insights into disease mechanisms, offering potential insights for future mechanistic studies and therapeutic exploration.

Keywords:  Alzheimer's disease; HIF-1α; bioinformatics analysis; microglia; neuroinflammation

DOI:  https://doi.org/10.1177/13872877251378007
J Neurochem. 2025 Sep;169(9): e70238

Dysregulation of Neuronal Activity-Dependent Immediate Early Genes in a Mouse Model of Angelman Syndrome.

Bhaskarjyoti Giri, Sagarika Das, Sudipta Jana, Nihar Ranjan Jana.

  Angelman syndrome (AS) is a debilitating neurodevelopmental disorder triggered by impaired function of the maternal UBE3A gene, which codes a protein that functions as a ubiquitin ligase and transcriptional coactivator. Ube3a maternal deficient mice replicate many key behavioral deficits associated with AS; however, the underlying molecular mechanisms remain poorly understood. Using an RT2 Profiler PCR array that summarizes the expression of 84 genes regulating synaptic plasticity, we identified a number of dysregulated genes in the visual cortex of AS mice brains at postnatal day 25 (P25) compared to wild-type animals. In-depth analysis revealed that various immediate early genes (IEGs), like Arc, Egr1-4, and Homer, are dramatically downregulated in the visual cortex of AS mice with regard to wild-type controls at P25. Moreover, the dark rearing of wild-type mice considerably decreased the levels of these IEGs to nearly the same level as those found in AS mice, along with the downregulation of Ube3a. Furthermore, a significant reduction in the expression of these IEGs can also be observed in the hippocampus of AS mice. Finally, we demonstrate that the augmented activity of Hdac2 in the AS mice brain might be connected with the downregulation of various IEGs and other synaptic plasticity-regulating genes. These findings indicate that the deregulated expression of neural activity-dependent IEGs could be linked with abnormal synaptic plasticity and associated behavioral deficits observed in AS mice.

Keywords:  Angelman syndrome; Hdac2; Ube3a; coactivator; immediate early gene

DOI:  https://doi.org/10.1111/jnc.70238
Acta Neuropathol. 2025 Sep 18. 150(1): 30

Limbic Alzheimer's co-pathology in multiple system atrophy is associated with cognitive impairment and diagnostic inaccuracy.

Janna van Wetering, Natasja A C Deshayes, Joëlle Boone, Inês Rodrigues Fernandes, Dagmar H Hepp, Henk W Berendse, Laura E Jonkman, Annemieke J M Rozemuller, Wilma D J van de Berg.

  The clinical heterogeneity of multiple system atrophy (MSA) may, along with the primary aggregation of alpha-synuclein (α-syn), partly be shaped by co-pathologies, such as amyloid-beta (Aβ), phosphorylated (p)-tau, and pTDP-43, though their relevance remains unclear. Here, we aimed to characterize the prevalence, morphology, regional patterns, and clinical relevance of co-pathologies in a well-characterized MSA autopsy cohort. Regional load (%area) and morphological characterization of α-syn (KM51), Aβ (6F/3D), p-tau (AT8), and pTDP-43 (pSer409) pathology were assessed in limbic regions of MSA (n = 70) donors from the Netherlands Brain Bank. APOE-ε4 genotyping and clinical parameters of the cohort were collected. Associations with clinical features were analyzed using ANCOVA and mixed linear models, adjusted for age and sex. Aβ, p-tau, and pTDP-43 pathology were detected in 31%, 91%, and 11% of all MSA cases, respectively, with the highest burdens in the entorhinal cortex and amygdala. Mixed MSA + AD cases had a higher age at death (75 ± 7 vs. 64 ± 7, p < 0.001), and more frequently APOE-ε4 alleles (p < 0.001) than pure MSA. Cognitive impairment (CDR scores) was associated with diffuse and compact Aβ plaques across all regions (r ≥ 0.24, p ≤ 0.015), p-tau pathology in CA1 and CA3 + 4 (r ≥ 0.32, p ≤ 0.020), and neuronal α-syn inclusions in the amygdala (r = 0.54, p < 0.001). No robust correlations were found between total α-syn burden and Aβ or p-tau. Misdiagnoses increased with co-pathology burden (Aβ: p = 0.040; p-tau: p = 0.020) and age at onset (80% in those with onset > 75 years). Our results demonstrate that limbic Aβ, p-tau, and neuronal α-syn pathologies occur in a substantial proportion of MSA donors and are independently associated with cognitive decline and diagnostic inaccuracy, particularly among those with older age at onset. By providing a systematic quantitative and morphological assessment of co-pathologies in limbic regions of MSA, our study advances beyond prior prevalence reports and highlights their direct clinical relevance. These findings highlight the need for refined diagnostic criteria and co-pathology-informed biomarker strategies for MSA.

Keywords:  Amyloid-beta; Co-pathology; Cognitive impairment; Diagnostic accuracy; Multiple system atrophy; Phosphorylated tau

DOI:  https://doi.org/10.1007/s00401-025-02940-0
J Alzheimers Dis. 2025 Sep 19. 13872877251378462

Role of ezrin-radixin-moesin proteins in the regulation of inflammatory cytokine expression in activated microglia.

Ayane Nakano, Shogo Maekawa, Takanori Murakami, Ayaka Fujimaki, Shinnosuke Takizawa, Junya Murata, Kazuki Ohuchi, Hisaka Kurita, Kazuyuki Takata, Masatoshi Inden.

  The ERM protein family, comprising ezrin, radixin, and moesin, mediates membrane-cytoskeleton interactions, regulating key cellular functions. This study investigated the expression of ERM proteins in microglia surrounding amyloid plaques in AppNL-F knock-in mice and their role in inflammatory responses. Moesin was predominantly localized to plaque-associated microglia, and in vitro knockdown experiments revealed distinct roles of ERM proteins in cytokine regulation. These findings suggest that each ERM protein contributes to microglial function through distinct mechanisms. Further elucidating the roles of individual ERM proteins in microglial function may lead to the identification of novel therapeutic targets for neurodegenerative diseases.

Keywords:  Alzheimer's disease; ERM protein; amyloid-β; microglia; neuroinflammatory

DOI:  https://doi.org/10.1177/13872877251378462
bioRxiv. 2025 Sep 04. pii: 2025.08.29.673049. [Epub ahead of print]

Neuroinflammatory crosstalk between microglia and astrocytes increases viral replication in an iPSC-derived model of CNS HIV infection.

James D Gesualdi, Jude Prah, Shiden Solomon, Jayden Cyrus, Ernesto Baçi, Peter J Gaskill, Çagla Akay-Espinoza, Kelly Jordan-Sciutto.

People living with HIV suffer multiple comorbid conditions related to chronic inflammation at increased rates compared to the general population, even when on effective antiretroviral therapy. In particular, current data indicate that the increased incidence and severity of neurocognitive impairment (NCI) are associated with unresolved neuroinflammation. Attempts to treat NCI in people living with HIV by reducing inflammation have thus far been unsuccessful, suggesting that a more mechanistic understanding of inflammatory processes in the CNS during HIV is necessary. Here, we use iPSC-derived microglia (iMg) and astrocytes (iAst) to model HIV infection in the CNS. We show that our iMg robustly express markers associated with microglial identity and are susceptible to HIV infection, but exhibit lower HIV replication rates and weaker immune response to HIV challenge compared to monocyte-derived macrophages. Coculture of iAst with iMg leads to a much stronger pro-inflammatory immune response, and, surprisingly, a robust increase in rates of HIV replication. Increased replication in iMg/iAst cocultures is associated with higher levels of multiple pro-inflammatory cytokines, including TNFα, which is produced by iAst upon exposure to HIV-infected iMg. Addition of exogenous TNFα to iMg during HIV infection is also sufficient to increase rates of replication, and neutralization of TNFα via adalimumab/Humira treatment in iMg/iAst cocultures reduces replication. Blocking NF-kB signaling with iKK inhibitor Bay-11-7082 (Bay-11) demonstrates that increased HIV replication in iMg/iAst cocultures is due to increased NF-kB activity. Finally, we show that in HIV-infected iMg there is movement of lysosomes to the periphery of the cell membrane and release of lysosomal content into the extracellular space, suggesting that this dysregulated lysosomal flux could further contribute to the pro-inflammatory microenvironment. We propose that this altered lysosomal trafficking and increased cytokine production drives a pro-inflammatory phenotype in glia and represents a potential source of unresolved neuroinflammation in people living with HIV.

DOI: https://doi.org/10.1101/2025.08.29.673049