bims-micgli Biomed News
on Microglia
Issue of 2025–12–07
forty-six papers selected by
Matheus Garcia Fragas, Universidade de São Paulo
  1. Loss of PILRA promotes microglial immunometabolism to reduce amyloid pathology in cell and mouse models of Alzheimer's disease.
  2. Amyloidosis of bridging veins is a pathologic feature of Alzheimer's disease.
  3. DAP12 deletion reduces neuronal SLIT2 and demyelination and enhances brain resilience in female tauopathy mice.
  4. Prediction of continuous amyloid positron emission tomography with fluid measures of phosphorylated tau and β-amyloid.
  5. A unique microglia subset associated with aggressive α-synucleinopathy uncovered in a rapidly progressive multiple system atrophy cerebellar type model.
  6. Genetic dissection of microglia cannibalism reveals an IL10 signaling axis controls microglia lifespan.
  7. Siponimod inhibits disease-associated microglia-T cell interactions in chronic experimental autoimmune encephalomyelitis.
  8. Targeting Microglial Activation to Modulate Neuroinflammation in Alzheimer's Disease.
  9. Clinical Validation of Novel Immunoassays for Plasma Phosphorylated Tau 217, 212, 181, 231, and Brain-Derived Tau Across the Biochemical Spectrum of Alzheimer's Disease.
  10. Oxidized phosphatidylcholines deposition drives chronic neurodegeneration in a mouse model of progressive multiple sclerosis via IL-1β signaling.
  11. APOE E4 Alzheimer's Risk Converges on an Oligodendrocyte Subtype in the Human Entorhinal Cortex.
  12. Microglial lipid droplets as therapeutic targets in age-related neurodegenerative diseases.
  13. P2Y12 Receptor Function Governs Microglial Surveillance and Cell-Cell Interactions in the Cerebral Cortex.
  14. Genetic Reduction of the Translational Repressors FMRP and 4E-BP2 Preserves Memory in Mouse Models of Alzheimer's Disease.
  15. Characterization of the brain lipidome associated with frontotemporal lobar degeneration MAPT P301S mutation.
  16. Sex-Specific Molecular Architecture of Microglia-Mediated Neuronal Pruning Across the Human Lifespan.
  17. Astrocytic Interleukin-33 Deficiency Reduces Glial Fibrillary Acidic Protein Expression and Exacerbates Microglial Activation and Neuronal Damage in a Chemically Induced Inflamed Frontal Cortex.
  18. Microgliopathy as a primary mediator of neuronal death in models of Friedreich's Ataxia.
  19. Stratification of brain-derived extracellular vesicles of Alzheimer's disease patients indicates a unique proteomic content and a higher seeding capacity of small extracellular vesicles.
  20. Microglial phagoptosis in development, health, and disease.
  21. Probing tau citrullination in Alzheimer's disease brains and mouse models of tauopathy.
  22. Aberrant neural activity in the peritumoral cortex underlies the progression of tumor-associated seizures.
  23. Dietary lipid content modifies wah-1/AIFM1-associated phenotypes via LRK-1 and DRP-1 expression in C. elegans.
  24. High throughput identification of genetic regulators of microglial inflammatory processes in Alzheimer's disease.
  25. Copper regulates the expression of immune genes in microglial cells in vitro.
  26. Nucleolar aggregation of key neuropathological proteins in the postmortem neurodegenerative brain.
  27. Laminar organization of pyramidal neuron cell types defines distinct CA1 hippocampal subregions.
  28. Leucine-Rich Repeat Kinase 2 Relates to Neuroaxonal Degeneration via Tau Pathology and Microglial Activation in Alzheimer's Disease.
  29. Altered Mechanical Properties of Astrocytes Lacking MLC1: Implications for the Leukodystrophy MLC.
  30. APIP regulates the priming of canonical NLRP3 and non-canonical Caspase-11/4 inflammasomes by binding to TRAF6.
  31. NG2-Glia Heterogeneity Across Cortical Layers.
  32. A distinct PP2A subunit regulates local protein phosphorylation at the axon initial segment.
  33. Chronic Styrene Exposure Causes Oxidative Stress, Neuroinflammation, and Hippocampal Memory Dysfunction via NLRP3 Inflammasome Activation.
  34. Longitudinal proteomic profiling of cerebrospinal fluid in untreated multiple sclerosis defines evolving disease biology.
  35. Astrocytic TCF7L2 Impacts Brain Osmoregulation and Restricts Neuronal Excitability.
  36. Human oligodendrocyte progenitor cells mediate synapse elimination through TAM receptor activation.
  37. Tau-targeting active immunotherapy slows progression and reduces pathology in mouse models of tauopathy.
  38. SerpinA3N-APOE interaction in astrocytes exacerbates Alzheimer's disease progression through NFκB activation.
  39. Single-cell analysis reveals shared and distinct molecular signatures in brain organoid models of neurodegeneration and neuroinflammation.
  40. Extracellular vesicles released from Marek's disease virus-transformed T-cells impact immune cell proliferation.
  41. Transcriptome analysis reveals reduced lipid accumulation and mitochondrial metabolic remodeling in ADCY3-overexpressing adipocytes.
  42. Astrocyte activation persists one year after TBI: a dynamic shift from inflammation to neurodegeneration.
  43. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Alzheimer's Disease: Recent Advances and Controversies.
  44. Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.
  45. The 'silent' brain cells that shape our behaviour, memory and health.
  46. Experiences of participant burden in an Alzheimer's disease research center longitudinal cohort.
  1. Sci Transl Med. 2025 Dec 03. 17(827): eadw7428
    Loss of PILRA promotes microglial immunometabolism to reduce amyloid pathology in cell and mouse models of Alzheimer's disease.
    Tanya N Weerakkody, Hanna Sabelström, Shan V Andrews, Jean Paul Chadarevian, Marcus Y Chin, David Tatarakis, Nicholas E Propson, Do Jin Kim, Richard Theolis, Gian Carlo G Parico, Hiwot Misker, Jennifer E Kung, Abira Bandyopadhyay, Yaneth Robles Colmenares, Taggra-Nicole Jackson, Ahlam N Qerqez, Srijana Balasundar, Sonnet S Davis, Connie Ha, Rajarshi Ghosh, Ritesh Ravi, Anil Rana, Kyla Germain, Arnold Tao, Ken Xiong, Dylan Braun, Karthik Raju, Kang-Chieh Huang, Lihong Zhan, Jing L Guo, Hoda Safari Yazd, Lily Sarrafha, Joia Kai Capocchi, Jonathan Hasselmann, Alina L Chadarevian, Christina Tu, Kimiya Mansour, Ghazaleh Eskandari-Sedighi, Niccolò Tesi, Sven van der Lee, Marc Hulsman, Georgii Oshegov, Yolande Pijnenburg, Meredith Calvert, Henne Holstege, Jung H Suh, Gilbert Di Paolo, Hayk Davtyan, Joseph W Lewcock, Mathew Blurton-Jones, Kathryn M Monroe.
      The Alzheimer's disease (AD) genetic landscape identified microglia as a key disease-modifying cell type. Paired immunoglobulin-like type 2 receptor alpha (PILRA) is an immunoreceptor tyrosine-based inhibitory motif domain-containing inhibitory receptor, expressed by myeloid cells such as microglia. The known protective PILRA G78R gene variant reduces AD risk in apolipoprotein E4 (APOE4) carriers and is enriched in a cohort of healthy centenarians. However, mechanisms underlying protective effects in microglia are undefined. Here, we identified biological functions of PILRA in human induced pluripotent stem cell-derived microglia (iMG) and chimeric AD mice. PILRA knockout (KO) in iMG rescued ApoE4-mediated immunometabolic deficits and prevented lipotoxicity through increased lipid storage, improved mitochondrial bioenergetics, and antioxidant activity. PILRA KO also enhanced microglial chemotaxis and attenuated inflammation. With pharmacological inhibitor studies, we showed that peroxisome proliferator-activated receptor and signal transducer and activator of transcription 1/3 mediated PILRA-dependent microglial functions. AD mice transplanted with human PILRA KO microglia exhibited reduced amyloid pathology and rescued synaptic markers. A high-affinity ligand blocking PILRA antibody phenocopied PILRA KO iMG. These findings suggest that PILRA is a pharmacologically tractable therapeutic target for AD.
    DOI:  https://doi.org/10.1126/scitranslmed.adw7428
  2. J Exp Med. 2026 Feb 02. pii: e20251860. [Epub ahead of print]223(2):
    Amyloidosis of bridging veins is a pathologic feature of Alzheimer's disease.
    Leon C D Smyth, Daan Verhaege, Elio Standen-Bloom, Yue Wu, Yiming Gan, Steffen E Storck, Pavle Boskovic, Benjamin A Plog, Tornike Mamuladze, Jose A Mazzitelli, Zhuoying Wang, Daniel D Lee, Gwendalyn J Randolph, Antoine Drieu, Katherine E Schwetye, Song Hu, Daniel S Reich, Douglas H Kelley, Rupal I Mehta, Jonathan Kipnis.
      Alzheimer's disease (AD) is characterized by the accumulation of extracellular aggregated amyloid beta, resulting from impaired waste clearance. We recently identified new cerebrospinal fluid (CSF) efflux structures termed arachnoid cuff exit (ACE) points and speculated that these may be impacted in AD, leading to impaired waste clearance function. Using 5XFAD mice, we found progressive amyloidosis of bridging veins at ACE points. Indeed, in 5XFAD mice, there is impaired CSF efflux to the dura mater, impaired CSF flow along bridging veins, and impaired blood flow through bridging veins. These observations suggest that ACE point amyloidosis plays a role in waste clearance dysfunction in AD. In postmortem human samples, we also found striking amyloidosis of the bridging veins of individuals with AD. Moreover, in human AD specimens, there was prominent bridging vein structural degeneration, indicating advanced pathology and stronger deficits in humans. We propose that bridging vein amyloidosis is an underrecognized pathophysiological correlate of AD that may impair CSF efflux, intracranial pressure, vascular reactivity, and vascular integrity.
    DOI:  https://doi.org/10.1084/jem.20251860
  3. Mol Neurodegener. 2025 Dec 02. 20(1): 124
    DAP12 deletion reduces neuronal SLIT2 and demyelination and enhances brain resilience in female tauopathy mice.
    Hao Chen, Li Fan, Qi Guo, Man Ying Wong, Jingjie Zhu, Nessa Foxe, Winston Wang, Aviram Nessim, Gillian Carling, Bangyan Liu, Chloe Lopez-Lee, Yige Huang, Sadaf Amin, Tark Patel, Sue-Ann Mok, Won-Min Song, Bin Zhang, Shiaoching Gong, Qin Ma, Hongjun Fu, Li Gan, Wenjie Luo.
       BACKGROUND: Pathogenic tau accumulation drives neurodegeneration in Alzheimer's disease (AD). Enhancing the aging brain's resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12), highly and selectively expressed by microglia, plays a crucial role in microglial immune responses. Previous studies have shown that tauopathy mice lacking DAP12 exhibit higher tau pathology but are protected from tau pathology-induced cognitive deficits. However, the exact mechanism behind this resilience remains elusive.
    METHODS: We investigated the effects of DAP12 deletion on tau pathology, as well as tau-induced brain inflammation and neurodegeneration, in homozygous human Tau P301S transgenic mice. In addition, we conducted single-nucleus RNA sequencing of hippocampal tissues to examine cell type-specific transcriptomic changes at the single-cell level. Furthermore, we utilized the CellChat package to profile cell-cell communication in the mouse brain and investigated how these interactions are affected by tau pathology and Dap12 deletion.
    RESULTS: We demonstrated that Dap12 deletion reduced tau processing in primary microglia and increased tau pathology in female tauopathy mice, with minimal effects on males. Despite this, Dap12 deletion markedly reduced brain inflammation, synapse loss, and demyelination, indicating enhanced resilience to tau toxicity. Single-cell transcriptomic profiling revealed that Dap12 deletion blocked tau-induced alterations in microglia, neurons, and oligodendrocytes. CellChat analysis identified aberrant tau-induced SLIT2 signaling from excitatory neurons to oligodendrocytes. Dap12 deletion suppressed Slit2 upregulation and mitigated demyelination, while lentiviral-Slit2 overexpression induced myelin loss in tauopathy mice. Elevated SLIT2 levels were associated with demyelination in tauopathy mouse model and human AD brains. Spatial transcriptomics revealed a spatial correlation of SLIT2 expression and tau pathology in AD brain tissue.
    CONCLUSIONS: Our study identifies a novel DAP12-dependent mechanistic link between upregulated Slit2 expression in excitatory neurons and oligodendrocyte-dependent myelination loss in tauopathy. Despite elevating tau load, the absence of microglial Dap12 ameliorates neuroinflammation and improves brain functions in tauopathy mice. Our study suggests that selectively targeting the toxic aspects of DAP12 signaling while preserving its beneficial functions may be a promising strategy to enhance brain resilience in AD.
    Keywords:  Brain resilience; DAP12; Demyelination; SLIT2; Tau toxicity, oligodendrocytes
    DOI:  https://doi.org/10.1186/s13024-025-00903-3
  4. EMBO Mol Med. 2025 Dec 01.
    Prediction of continuous amyloid positron emission tomography with fluid measures of phosphorylated tau and β-amyloid.
    Niklas Mattsson-Carlgren, Linda Karlsson, Weizhong Tang, Kaj Blennow, Henrik Zetterberg, Randall J Bateman, Suzanne E Schindler, Nicolas Barthelemy, Sebastian Palmqvist, Erik Stomrud, Shorena Janelidze, Oskar Hansson.
      Brain amyloid-β (Aβ) pathology is a core feature of Alzheimer disease (AD) and can be quantified using positron emission tomography (PET). Cerebrospinal fluid (CSF) and plasma biomarkers detect abnormal Aβ, but it is unclear to what degree they can predict quantitative Aβ-PET. We explored plasma and CSF biomarkers in relation to Aβ-PET in the BioFINDER-2 study (N = 1053), and the BioFINDER-1 study (N = 238). We developed a machine learning pipeline to predict Aβ-PET using CSF and plasma measures. The best models achieved R2 = 0.79. Plasma P-tau217 and CSF Aβ42/Aβ40 contributed the most. CSF Aβ42/Aβ40 contributed most to identify Aβ-positivity, while continuous Aβ-PET load within the positive range was best predicted by plasma P-tau217. Models using only plasma measures approached performance of CSF models. Altered metabolism of soluble Aβ may be highly associated with presence of Aβ plaques, while soluble P-tau217 levels may continue to change during build-up of Aβ pathology.
    Keywords:  Alzheimer’s Disease; Amyloid; Clinical Trials; PET; Plasma Biomarkers
    DOI:  https://doi.org/10.1038/s44321-025-00348-7
  5. Neurobiol Dis. 2025 Nov 29. pii: S0969-9961(25)00423-1. [Epub ahead of print]218 107206
    A unique microglia subset associated with aggressive α-synucleinopathy uncovered in a rapidly progressive multiple system atrophy cerebellar type model.
    Dai Matsuse, Hiroo Yamaguchi, Masaya Harada, Yuu-Ichi Kira, Yuji Nishimura, Katsuhisa Masaki, Tatsunori Tanaka, Toru Saiga, Kei Fujishima, Eriko Matsuo, Ryo Yamasaki, Noriko Isobe, Jun-Ichi Kira.
      Multiple system atrophy (MSA) is a progressive and fatal α-synucleinopathy characterized by α-synuclein-positive (α-syn+) glial cytoplasmic inclusions in oligodendrocytes. The cerebellar variant (MSA-C) primarily affects olivopontocerebellar fibers, resulting in extensive demyelination and glial activation. To model this pathology, we developed a Tet-Off-based MSA-C mouse model with oligodendrocyte-specific overexpression of human A53T α-syn. Upon doxycycline withdrawal at 8 weeks of age, mice developed progressive cerebellar ataxia by 26 weeks and succumbed by 30 weeks. These mice exhibited severe demyelination and marked activation of microglia and astroglia in the brainstem and cerebellum, along with widespread propagation of α-syn oligomers and phosphorylated α-syn (p-α-syn) aggregates in oligodendrocytes, astrocytes, and neurons. Single-cell RNA sequencing of CD11b+ cells from the brain and spinal cord identified a distinct microglial cluster expressing Toll-like receptor 2 (Tlr2), transglutaminase 2 (Tgm2), arginase-1, macrophage scavenger receptor-1 (Msr1), inflammatory genes (such as Nfkbia, Nfkbiz, and Il1b), and chemokines (including Ccl3, Ccl4, and Ccl12). These microglia were located adjacent to p-α-syn aggregates and were distinct from previously described protective disease-associated microglia and border-associated macrophages. TLR2- and TGM2+Iba1+ microglia were particularly enriched in demyelinating lesions. Prophylactic administration of the CSF1R inhibitor BLZ945 exacerbated motor deficits and demyelination, significantly increasing this microglial population. Similarly, MSR1+ and CD68+ microglia/macrophages were observed in early pontocerebellar lesions of six human MSA-C autopsy cases. These findings suggest that this pro-inflammatory microglia subset plays a central role in disease progression and may represent a promising therapeutic target for modifying the course of MSA-C and related synucleinopathies.
    Keywords:  Demyelination; Microglia; Multiple system atrophy; Single-cell RNA sequencing; Tet-off system; Transgenic mouse model; Α-Synuclein
    DOI:  https://doi.org/10.1016/j.nbd.2025.107206
  6. bioRxiv. 2025 Nov 21. pii: 2025.11.21.689277. [Epub ahead of print]
    Genetic dissection of microglia cannibalism reveals an IL10 signaling axis controls microglia lifespan.
    Hannah Gordon, Dailin Gan, Antonio Dolojan, John Dennen, Camden A Hoover, Zachary M Koh, Khang Chau, Ricky Avalos Arceo, Cara Cavanaugh, Jun Li, Cody J Smith.
      The development of complex organs, like the brain, demands a robust system for tissue remodeling and cellular debris clearance. In the brain, this function is performed by microglia, which must clear diverse debris substrates, including that caused by cell death. Although the subsequent fate of these phagocytic microglia is a critical regulatory point that impacts whether the brain resolves a debris environment, the genetic mechanisms that control microglia fate after debris clearance remain mostly unknown. To address this, we conducted a large-scale CRISPR screen in zebrafish using a custom-built robotic confocal microscope. We selected candidate genes from a single-cell RNA sequencing dataset of embryonic mouse microglia. This screen identified several modulators of microglial lifespan and cannibalism that are enriched in mouse and zebrafish microglia, including interleukin-10 receptor beta ( il10rb ), a receptor subunit for the cytokine IL10. Perturbation of il10 , il10rb, and downstream signaling molecules JAK/STAT in zebrafish reduced microglial death. Expression analysis in mouse and zebrafish confirmed that microglia express both il10 and il10rb . Given the established role of IL10 in lysosomal remodeling, we hypothesized that it regulates microglial survival through lysosomal acidification. While il10rb perturbation did not alter lysosome number or size, it caused a significant reduction in LysoTracker-positive lysosomes, indicating decreased lysosomal acidification. Inhibiting v-ATPase also reduced microglial death, reinforcing the link between lysosomal pH and cell fate. Our findings reveal a cytokine-regulated mechanism where lysosomal dynamics determine the survival of phagocytic microglia. We propose that a necroptosis-cannibalism process functions as a quality control mechanism for microglial turnover, which is critical for refining neuroimmune cell function in the brain.
    DOI:  https://doi.org/10.1101/2025.11.21.689277
  7. Acta Neuropathol Commun. 2025 Dec 01. 13(1): 247
    Siponimod inhibits disease-associated microglia-T cell interactions in chronic experimental autoimmune encephalomyelitis.
    Leila Husseini, Anastasia Geladaris, Marlene C J Steinleitner, Darius Häusler, Martin S Weber.
      Chronically inflamed, reactive microglia represent a prominent feature of secondary progressive multiple sclerosis (SPMS). Especially their interplay with encephalitogenic T cells promotes neuroaxonal damage associated with disease progression. In our study, we aimed to explore the potential of siponimod, a sphingosine-1-phosphate modulator approved for the treatment of active SPMS, to inhibit disease-associated T cell-microglia interactions using a chronic murine experimental autoimmune encephalomyelitis (EAE) model of MS. We found that therapeutic siponimod treatment of chronic EAE improved clinical severity accompanied by reduced demyelination and neuroaxonal damage, diminished CNS T cell infiltration and altered proinflammatory microglia responses. This effect was partly attributed to a direct effect on microglia, as siponimod pretreatment inhibited interferon-γ-elicited responses of primary mouse microglia in vitro and limited their ability to induce T cell activation and proliferation in T cell-microglia co-cultures. Additionally, we observed reduced peripheral T cell numbers in our EAE model, with a pronounced shift to immunosenescent and regulatory T cell subsets, a pattern which we similarly detected in a cohort of SPMS patients following siponimod treatment. These findings indicate that siponimod dampens compartmentalized CNS inflammation by disrupting detrimental interactions between T cells and microglia through a dual central and peripheral mechanism of action.
    Keywords:  Microglia; Multiple sclerosis; Neurodegeneration; Progression; Siponimod
    DOI:  https://doi.org/10.1186/s40478-025-02136-3
  8. Neuromolecular Med. 2025 Dec 04. 27(1): 76
    Targeting Microglial Activation to Modulate Neuroinflammation in Alzheimer's Disease.
    Vinay Patil, Amit Sharma, Bhavin Parekh, Husni Farah, S Renuka Jyothi, Swati Mishra, Anima Nanda, Shaker Al-Hasnaawei, Manoj Kumar Mishra.
      Alzheimer's disease is a multifaceted neurodegenerative condition marked by the build-up of amyloid plaques and neurofibrillary tangles that lead to progressive cognitive impairment. Neuroinflammation, especially the activation of microglia, plays a pivotal part in driving this pathology. Microglia are the brain's resident immune cells and can adopt a spectrum of activation states that support either neuroprotection or neurodegeneration. Evidence shows that their phenotypes are highly dynamic and shaped by environmental influences and pathological signals. During the early phases of the disease, microglia tend to assume anti-inflammatory roles that facilitate plaque clearance and promote tissue recovery. Prolonged or dysregulated activation, however, shifts them toward a pro-inflammatory state that amplifies neuronal damage. Several molecular pathways including JAK STAT, PI3K AKT, and MAPK are central to regulating these processes and have emerged as promising therapeutic targets. This review summarizes current insights into microglial phenotypic transitions, the signaling mechanisms governing their activation, and the therapeutic potential of modulating neuroinflammation. Enhancing the neuroprotective capacity of microglia, suppressing chronic inflammatory responses, and targeting key receptors such as TREM2 and P2 × 7 represent potential strategies. A deeper understanding of microglial interactions with other glial cells and the molecular drivers of their activation may provide new avenues for slowing or halting the progression of Alzheimer's disease and related neurodegenerative disorders.
    Keywords:  Alzheimer’s disease; Microglia; Neurodegeneration; Neuroinflammation; Therapeutic strategies
    DOI:  https://doi.org/10.1007/s12017-025-08898-2
  9. J Neurochem. 2025 Dec;169(12): e70313
    Clinical Validation of Novel Immunoassays for Plasma Phosphorylated Tau 217, 212, 181, 231, and Brain-Derived Tau Across the Biochemical Spectrum of Alzheimer's Disease.
    Maciej Dulewicz, Przemysław Radosław Kac, Fernando Gonzalez Ortiz, Thomas K Karikari, Agnieszka Kulczyńska-Przybik, Barbara Mroczko, Michael Turton, Peter Harrison, Manuel Maler, Timo Oberstein, Johannes Kornhuber, Jörg Hanrieder, Henrik Zetterberg, Kaj Blennow, Piotr Lewczuk.
      Plasma biomarkers have emerged as promising less invasive alternatives for Alzheimer's disease (AD) detection. However, the diagnostic performance of phosphorylated tau (p-tau) isoforms remains incompletely validated. In a cohort of 160 patients from a memory clinic, plasma levels of p-tau217, p-tau212, p-tau181, p-tau231, and BD-tau were measured using Single Molecule Array (Simoa) in-house assays, alongside NFL and GFAP. Subjects were classified using the Erlangen Score into Controls (n = 53), neurochemically possible AD (n = 27), and probable AD (n = 80). Plasma concentrations of all p-tau isoforms were significantly elevated in both Possible AD and Probable AD groups compared to Controls (p < 0.001). Notably, p-tau217 exhibited the highest diagnostic accuracy (AUC = 0.954) and correlated with CSF classical biomarkers. A positive result for p-tau217 increases the probability of AD almost fivefold. Plasma p-tau217 reflects AD neurochemical changes and has high negative predictive value, supporting its use as a screening tool. However, moderate PPV suggests the need for confirmatory testing to ensure an accurate diagnosis.
    Keywords:  Alzheimer's disease; GFAP; NFL; diagnostic accuracy; neurodegeneration; phosphorylated tau; plasma biomarkers; p‐tau217
    DOI:  https://doi.org/10.1111/jnc.70313
  10. Nat Neurosci. 2025 Dec 01.
    Oxidized phosphatidylcholines deposition drives chronic neurodegeneration in a mouse model of progressive multiple sclerosis via IL-1β signaling.
    Ruoqi Yu, Brian M Lozinski, Ally Seifert, Khanh Ta, Stephanie Zandee, Deepak K Kaushik, Jian Park, Wendy Klement, Sandra Larouche, Sotirios Tsimikas, Joseph L Witztum, Dorian B McGavern, Alexandre Prat, Yifei Dong.
      Oxidized phosphatidylcholines (OxPCs) are neurotoxic byproducts of oxidative stress elevated in the central nervous system (CNS) during progressive multiple sclerosis (P-MS). How OxPCs contribute to the pathophysiology of P-MS is unclear. Here we show that stereotactic OxPC deposition in the CNS of mice induces a chronic compartmentalized lesion with pathological features similar to chronic active lesions found in P-MS. Using this model, we found that although microglia protected the CNS from chronic neurodegeneration, they were also replaced by monocyte-derived macrophages in chronic OxPC lesions. Aging, a risk factor for P-MS, altered microglial composition and exacerbated neurodegeneration in chronic OxPC lesions. Amelioration of disease pathology in Casp1/Casp4-deficient mice and by blockade of IL-1R1 indicate that IL-1β signaling contributes to chronic OxPC accumulation and neurodegeneration. These results highlight OxPCs and IL-1β as potential drivers of chronic neurodegeneration in MS and suggest that their neutralization could be effective for treating P-MS.
    DOI:  https://doi.org/10.1038/s41593-025-02113-y
  11. bioRxiv. 2025 Nov 20. pii: 2025.11.20.689483. [Epub ahead of print]
    APOE E4 Alzheimer's Risk Converges on an Oligodendrocyte Subtype in the Human Entorhinal Cortex.
    Louise A Huuki-Myers, Heena R Divecha, Svitlana V Bach, Madeline R Valentine, Nicholas J Eagles, Bernard Mulvey, Rahul A Bharadwaj, Ruth Zhang, James R Evans, Melissa Grant-Peters, Ryan A Miller, Joel E Kleinman, Shizhong Han, Thomas M Hyde, Stephanie C Page, Daniel R Weinberger, Keri Martinowich, Mina Ryten, Kristen R Maynard, Leonardo Collado-Torres.
      The entorhinal cortex (ERC) is implicated in early progression of Alzheimer's disease (AD). Here we investigated the impact of established biological risk factors for AD, including APOE genotype (E2 versus E4 alleles), sex, and ancestry, on gene expression in the human ERC. We generated paired spatially-resolved transcriptomics (SRT) and single-nucleus RNA sequencing data (snRNA-seq) in postmortem human ERC tissue from middle aged brain donors with no history of AD. APOE -dependent changes in gene expression predominantly mapped to a transcriptionally-defined oligodendrocyte subtype, which varied substantially with ancestry, and suggested differences in oligodendrocyte differentiation and myelination. Integration of SRT and snRNA-seq data identified a common gene expression signature associated with APOE genotype, which we localized to the same oligodendrocyte subtype and a white matter spatial domain. This suggests that AD risk in ERC may be associated with disrupted oligodendrocyte function, potentially contributing to future neurodegeneration.
    Lay Summary: Alzheimer's disease (AD) is a neurodegenerative disorder that accounts for 60-80% dementia cases. Apolipoprotein E ( APOE) genotype is the strongest genetic risk factor for AD, and the entorhinal cortex (ERC) is a brain region implicated in its earliest progression. Our study investigated how APOE genotype impacts gene expression in the ERC. We identified genotype-dependent effects on oligodendrocytes with different transcriptional profiles related to maturation that may help explain how APOE genotype mediates its effects on AD risk.
    DOI:  https://doi.org/10.1101/2025.11.20.689483
  12. NPJ Aging. 2025 Nov 30.
    Microglial lipid droplets as therapeutic targets in age-related neurodegenerative diseases.
    Soyoung Sung, Hui-Ju Kim, Sun Joo Cha, Minyeop Nahm, Seung Hyun Kim, Min-Soo Kwon.
      Monoclonal antibodies approved for Alzheimer's disease (AD), such as lecanemab and aducanumab, have been shown to enhance microglial phagocytic function, underscoring the therapeutic relevance of microglia in neurodegenerative diseases (NDDs). Emerging evidence implicates lipid droplets (LDs) in brain aging and NDDs, particularly through LDs-laden microglia known as lipid droplet-accumulating microglia (LDAM), which exhibit impaired phagocytosis, elevated oxidative stress, and dysregulated lipid metabolism. Among microglial subtypes identified through transcriptomic and functional profiling-including disease-associated microglia (DAM), microglia in neurodegenerative disease (MGnD), white matter-associated microglia (WAM), and dark microglia-LDs-laden microglia have clear metabolic signatures defined by excessive LDs accumulation and disrupted lipid turnover. Here, we discuss the biogenesis of LDs, their pathological accumulation in microglia, and the therapeutic potential of targeting LDs. We further propose a hypothetical mechanism by which LDs clearance restore energy metabolism, nuclear transport, facilitate DNA repair, suppress inflammation, and phagocytosis in microglia. Thus, elucidating LDs dynamics in microglia may provide novel therapeutic avenues for modifying the course of NDDs.
    DOI:  https://doi.org/10.1038/s41514-025-00295-0
  13. Glia. 2026 Feb;74(2): e70109
    P2Y12 Receptor Function Governs Microglial Surveillance and Cell-Cell Interactions in the Cerebral Cortex.
    Balázs Pósfai, Eszter Szabadits, Csaba Cserép, Sára Vida, Anett D Schwarcz, Rebeka Fekete, Krisztina Tóth, Orsolya Bánkövi, Cecília Szekeres-Paraczky, Zsófia Maglóczky, Katinka Lakatos-Ujvári, Anna Kellermayer, Ana Rita Brás, Péter Gombás, Lóránd Erőss, Ádám Dénes.
      Microglia are unique damage sensors of the central nervous system, and their homeostatic roles are increasingly recognized. Purinergic signaling through the P2Y12 receptor (P2Y12R) is indispensable for directed process movement of microglia in response to danger-related ATP release. P2Y12R has also been shown to modulate microglial communication with neurovascular elements in the brain and to profoundly influence outcomes in experimental models of brain injury. However, the exact role of P2Y12R in shaping microglial phenotypes and interactions under physiological conditions remains unresolved due to disagreements between ex vivo and in vivo observations. Using in vivo 3D two-photon imaging and high-resolution anatomy we show that P2Y12Rs are essential regulators of microglial physiology, fundamentally shaping homeostatic microglial surveillance activity and direct contacts with other cell types. Genetic deletion or acute pharmacological blockade of P2Y12R function leads to altered surveillance activity, microglial morphology and P2Y12R nanoclustering, resulting in changes of direct microglial contacts with neuronal cell bodies, smooth muscle-bearing blood vessels and oligodendrocyte processes in the somatosensory cortex of mice. Furthermore, molecular anatomy of P2Y12R expression shows correlation with disease severity and altered microglia-neuron interactions in human epilepsy. Thus, our results identify P2Y12Rs as major participants in microglial physiology whose dysfunction could impact defined cell-cell interactions in different neurological states.
    Keywords:  clustering; direct contact; epilepsy; homeostasis; in vivo imaging; microglial physiology; morphology
    DOI:  https://doi.org/10.1002/glia.70109
  14. Aging Cell. 2025 Dec 03. e70315
    Genetic Reduction of the Translational Repressors FMRP and 4E-BP2 Preserves Memory in Mouse Models of Alzheimer's Disease.
    Felipe C Ribeiro, Danielle Cozachenco, Michael Parkhill, Brandon Rodrigue, Caio Borges, Jean-Claude Lacaille, Karim Nader, Fernanda G De Felice, Mychael V Lourenco, Argel Aguilar-Valles, Nahum Sonenberg, Sergio T Ferreira.
      Alzheimer's disease (AD) is characterized by progressive memory decline. Converging evidence indicates that hippocampal mRNA translation (protein synthesis) is defective in AD. Here, we show that genetic reduction of the translational repressors, Fragile X messenger ribonucleoprotein (FMRP) or eukaryotic initiation factor 4E (eIF4E)-binding protein 2 (4E-BP2), prevented the attenuation of hippocampal protein synthesis and memory impairment induced by AD-linked amyloid-β oligomers (AβOs) in mice. Moreover, genetic reduction of 4E-BP2 rescued memory deficits in aged APPswe/PS1dE9 (APP/PS1) transgenic mouse model of AD. Our findings demonstrate that strategies targeting repressors of mRNA translation correct hippocampal protein synthesis and memory deficits in AD models. Results suggest that modulating pathways controlling brain mRNA translation may confer memory benefits in AD.
    Keywords:  4E‐BP2; Alzheimer's disease; fragile X messenger ribonucleoprotein; mRNA translation; memory
    DOI:  https://doi.org/10.1111/acel.70315
  15. J Lipid Res. 2025 Nov 27. pii: S0022-2275(25)00215-9. [Epub ahead of print] 100952
    Characterization of the brain lipidome associated with frontotemporal lobar degeneration MAPT P301S mutation.
    Almudena Maroto Juanes, Thomas Vogels, Sascha Koppes-den Hertog, Maarten Loos, Dieter Lütjohann, Martin Giera, Rik van der Kant.
      Mutations in microtubule-associated protein Tau (MAPT), the gene that codes for the protein Tau, cause frontotemporal lobar degeneration (FTLD) with phenotypes ranging from behavioral changes to cognitive impairment and parkinsonism. Recently, lipid changes have been heavily implicated in synucleinopathies and secondary tauopathies such as Alzheimer's Disease (AD). Whether mutations in MAPT or accumulation of hyperphosphorylated Tau (pTau) can contribute to lipid changes in primary tauopathies is unknown. Here, we examine the effect of the FTLD-associated mutation MAPT P301S on brain lipid metabolism in a Tau transgenic mouse model. We find that the MAPT P301S mutation drives increased levels of diglycerides and hexosyl- and lactosylceramides while reducing triglycerides, specifically those triglyceride species containing monounsaturated fatty acids, but does not affect cholesterol metabolism prior to pTau accumulation. Strikingly, with increasing accumulation of pTau, neutral lipids such as cholesteryl esters and triglycerides start to accumulate in the brain of mutant mice, as also reported in the AD and FTLD brain. Furthermore, with increasing buildup of pTau, we observe a decrease in cholesterol synthesis and turnover to 24S-hydroxycholesterol. Overall our data indicates that Tau mutations strongly affect brain lipid metabolism.
    Keywords:  Cholesterol metabolism; Frontotemporal lobar degeneration; Lipidomics; Neutral lipids; Tau
    DOI:  https://doi.org/10.1016/j.jlr.2025.100952
  16. Mol Neurobiol. 2025 Dec 01. 63(1): 223
    Sex-Specific Molecular Architecture of Microglia-Mediated Neuronal Pruning Across the Human Lifespan.
    Cristina Sanfilippo, Paola Castrogiovanni, Rosa Imbesi, Michele Vecchio, Michelino Di Rosa.
      Sex-specific differences in neurodegenerative disease susceptibility suggest distinct molecular mechanisms underlying brain aging between males and females. In this study, we investigated transcriptomic profiles of complement system components, microglial markers, and astrocyte/neuronal proteins across the lifespan to elucidate sex-dependent synaptic pruning mechanisms. Comprehensive transcriptomic analysis was performed on brain tissue samples spanning multiple age groups and regions, examining expression patterns of complement genes (C1QA, C1QB, C1QC, C1R, C1S, C3, ITGAM, ITGB2), microglial markers (TMEM119, P2RY12, CSF1R, NLRP3, TREM2, AIF1), and astrocytic, neuronal, and tissue markers (MAP2, SYP, SNAP25, MAPT, GFAP, CHI3L1). Complement system components demonstrated pronounced sex bias. Males exhibited distinct U-shaped age-related patterns, with middle-late childhood (MLC) consistently showing the highest expression for most genes, decreasing in middle age, followed by partial reactivation in nonagenarians, and then a further reduction in centenarians. An oscillatory trajectory across the lifespan was observed in females, with a peak in centenarians. Regional analysis revealed diencephalic predominance and occipital suppression patterns. Microglial activation markers exhibited complex sex-dependent patterns, with males showing higher expression during childhood/adolescence and females demonstrating an elevation in advanced age. These genes displayed limbic and diencephalic enrichment with cerebellar reduction. Neuronal/astrocytic markers showed opposing trajectories: neuronal markers (MAP2, SNAP25, SYP, MAPT) generally declined with age, while astrocytic markers (GFAP, CHI3L1) increased. Males demonstrated compartmentalized gene clustering, while females showed integrated neuro-microglial networks. Functional enrichment analysis confirmed these networks coordinate complement-mediated synapse pruning, representing systematic age-related synaptic remodeling mechanisms that differ fundamentally between sexes and may influence neurodegenerative susceptibility patterns. These findings demonstrate that female brains maintain heightened complement-mediated synaptic pruning throughout aging, representing a double-edged mechanism that may confer adaptive plasticity while increasing vulnerability to neurodegeneration. Male brains exhibit more stable neuronal environments with reduced glial activation, potentially underlying sex-specific trajectories in brain aging and neurodegenerative disease susceptibility.
    Keywords:  Brain aging; Complement system; Microglial activation; Neuronal pruning; Sex differences
    DOI:  https://doi.org/10.1007/s12035-025-05547-4
  17. J Neurochem. 2025 Dec;169(12): e70310
    Astrocytic Interleukin-33 Deficiency Reduces Glial Fibrillary Acidic Protein Expression and Exacerbates Microglial Activation and Neuronal Damage in a Chemically Induced Inflamed Frontal Cortex.
    Yu-Chen Zheng, Wei-Yu Chen, Chih-Yen Wang, Shun-Fen Tzeng.
      Astrocytes, the most abundant glial cells in the CNS, play a crucial role in supporting neurons and respond to injury or disease through astrogliosis, a process marked by cellular hypertrophy and increased glial fibrillary acidic protein (GFAP) expression. Interleukin-33 (IL-33) was originally identified as an alarmin and is known to be produced by astrocytes and oligodendrocytes in the CNS. Recently, we reported its role in regulating oligodendrocyte differentiation. However, its role in astrocytes remains less defined. In a demyelinating mouse model induced by gliotoxin cuprizone (CPZ), IL-33 was previously shown to be reduced in oligodendrocytes within the corpus callosum. In this study, we found that lipopolysaccharide (LPS) stimulation enhanced nuclear IL-33 expression and GFAP production in cortical astrocytes. Using lentiviral-mediated IL-33 knockdown (IL33KD) and overexpression (IL33oe), we demonstrated that IL-33 positively regulates GFAP expression. Interestingly, we observed an increase in nuclear IL-33-expressing GFAP+ cortical astrocytes in CPZ-treated mice. In contrast, CPZ-induced GFAP upregulation in cortical astrocytes was abolished in IL-33 knockout (il33KO) mice. Furthermore, chronic CPZ feeding in il33KO mice led to increased microgliosis and neuronal damage within the frontal cortex, as well as abnormal anxiety-like behaviors. Collectively, these results indicate that elevated nuclear IL-33 in astrocytes under inflammatory conditions is critical for GFAP upregulation and astrogliosis. Loss of IL-33 disrupts astrocyte neuroprotective functions and glial reactivity in the frontal cortex, contributing to behavioral abnormalities under a demyelinating insult.
    Keywords:  IL‐33; astrocyte; cuprizone; demyelination; gliosis; microglia
    DOI:  https://doi.org/10.1111/jnc.70310
  18. Nat Commun. 2025 Nov 29.
    Microgliopathy as a primary mediator of neuronal death in models of Friedreich's Ataxia.
    Carla Pernaci, Avalon Johnson, Sydney Gillette, Anna S Warden, Chad McCormick, Sammy Weiser-Novak, Gabriela Ramirez, Emily H Broersma, Priyanka Mishra, Anusha Sivakumar, Stephanie Cherqui, Nicole G Coufal.
      Friedreich's ataxia (FRDA) is an incurable neurodegenerative disorder caused by a GAA repeat expansion in the frataxin (FXN) gene, leading to a severe reduction of the mitochondrial FXN protein, crucial for iron metabolism. While microglial inflammation is observed in FRDA, it remains unclear whether immune dysfunction is a primary disease mediator or a secondary reactionary phenotype. Utilizing patient-derived induced pluripotent stem cells (iPSCs), we report an intrinsic microglial phenotype of stark mitochondrial defects, iron overload, lipid peroxidation, and lysosomal abnormalities. These factors drive a pro-inflammatory state that contributes to neuronal death in co-culture systems. In a murine xenograft model, transplanted human FRDA microglia accumulate in white matter and the Purkinje cell layer, resulting in Purkinje neuron loss in otherwise healthy brains. Notably, CRISPR/Cas9-mediated correction of the GAA repeat reverses microglial defects and mitigates neurodegeneration. Here, we suggest that microglial dysfunction serve as a disease driver and a promising therapeutic target in FRDA.
    DOI:  https://doi.org/10.1038/s41467-025-66710-y
  19. Transl Neurodegener. 2025 Dec 05. 14(1): 63
    Stratification of brain-derived extracellular vesicles of Alzheimer's disease patients indicates a unique proteomic content and a higher seeding capacity of small extracellular vesicles.
    Marie Oosterlynck, Elodie Leroux, Balasubramaniam Namasivayam, Thomas Bouillet, Raphaelle Caillierez, Anne Loyens, Daniele Mazur, Romain Perbet, Christophe Lefebvre, Soulaimane Aboulouard, Claude-Alain Maurage, Bertrand Accart, Luc Buée, Morvane Colin.
       BACKGROUND: Alzheimer's disease (AD) is the most prominent form of dementia worldwide. It is characterized by tau lesions that spread throughout the brain in a spatio-temporal manner. This has led to the prion-like propagation hypothesis implicating a transfer of pathological tau seeds from cell to cell. Human brain-derived extracellular vesicles (BD-EVs) isolated from the brain-derived fluid of AD patients contain seeds that contribute to this tau pathology spreading. Knowing the rich diversity of EVs, isolation of functional EV sub-populations is required to unravel their implication in the pathophysiology of AD.
    METHODS: Here, enriched-small EVs (eSEVs) and enriched-large EVs (eLEVs) were isolated from frozen tissues after collagenase enzymatic brain dissociation to guarantee the best EVs' integrity. Then proteomic profiling and tau seeding capacity testing were performed in vitro and in vivo.
    RESULTS: BD-EVs were stratified according to their size (eSEVs and eLEVs) and characterized to define new markers specific to EVs in AD. Both AD-derived eSEVs and eLEVs show the presence of GWAS-associated proteins and indicate a specific AD pathophysiological signature. Notably, AD eSEVs contain more proteins relative to the integrin-mediated synaptic signaling, while AD eLEVs proteins were more related to respiratory electron transport and brain immunity. Injection of these vesicles in transgenic mouse brain revealed that the AD-derived eSEVs are more prone than eLEVs to participate in the prion-like propagation and hence represent an interesting therapeutic target.
    CONCLUSION: This study highlights the significant contribution of AD-derived EVs to tau propagation and provides new insights into different roles of EV sub-populations in AD.
    Keywords:  Alzheimer's disease; Clusterin; Collagenase brain dissociation; Extracellular vesicles; FERMT2; GWAS; Proteomic profiling; Tau seeding
    DOI:  https://doi.org/10.1186/s40035-025-00519-z
  20. Neurobiol Dis. 2025 Dec 01. pii: S0969-9961(25)00428-0. [Epub ahead of print]218 107211
    Microglial phagoptosis in development, health, and disease.
    Yuxuan Li, Shengbo Chen, Yi-Jun Liu.
      Microglial phagoptosis, defined as the phagocytosis of a viable cell by microglia that ultimately causes the death of the engulfed cell, has emerged as a pivotal process in sculpting neural circuits within the central nervous system (CNS). Essential for neurodevelopmental circuit refinement and ongoing tissue homeostasis, this process relies on dynamic molecular cues that direct microglia to specific cellular substrates. Physiologically, phagoptosis contributes to neural circuit refinement and cell number regulation during development; however, its dysregulation can drive neurodevelopmental and neurodegenerative disorders via aberrant cell removal. Recent advances have elucidated the distinct signaling pathways involved in target recognition and engulfment, revealing the dual roles of microglial phagoptosis in both CNS health and disease. Deeper mechanistic insight into this process offers new therapeutic opportunities for conditions characterized by defective or excessive cell clearance. This review summarizes current progress, highlights unresolved challenges, and discusses future perspectives on targeting microglial phagoptosis for intervention in CNS disorders.
    Keywords:  CNS homeostasis; Microglia; Neurodegeneration; Neurodevelopmental disorders; Phagoptosis
    DOI:  https://doi.org/10.1016/j.nbd.2025.107211
  21. Acta Neuropathol. 2025 Dec 05. 150(1): 61
    Probing tau citrullination in Alzheimer's disease brains and mouse models of tauopathy.
    Huimin Liang, Jerry B Hunt, Chao Ma, Andrii Kovalenko, John Calahatian, Cecelie Pedersen, Haiying Liu, Junyan Li, Malina Serrano, Danielle Blazier, Mallory Watler, Patricia Rocha-Rangel, Christopher Saunders, Laura J Blair, Leonid Breydo, Kevin Nash, Zainuddin Quadri, Brian Kraemer, Peter Nelson, Christopher Norris, Erin L Abner, Vladimir N Uversky, Dale Chaput, Maj-Linda B Selenica, Daniel C Lee.
      Alzheimer's disease (AD) includes a defining hallmark that correlates most closely to cognitive decline, namely misfolded tau protein. However, the "upstream" etiology and downstream clinical manifestations of tauopathies are quite diverse. Tau deposition elicits different pathological phenotypes and outcomes depending on the tau strain, proteoforms, and regional susceptibility. Posttranslational modifications (PTM) can alter tau structure, function, networks, and its pathological sequelae. We uncovered tau citrullination on multiple epitopes caused by peptidyl arginine deiminase (PAD) enzymes. PAD-induced citrullination irreversibly converts arginine residues to citrulline, producing a net loss of positive charge, elimination of pi-pi interactions, and increased hydrophobicity. We observed increased PAD2 and PAD4 in Alzheimer's disease (AD) brain and that they both can citrullinate tau. Tau can become citrullinated by PADs at all 14 arginine residues throughout the N-terminal domain (N-term), proline-rich domain (PR), microtubule-binding repeats domain (MBR), and C-terminal domain (C-term) on full-length tau (2N4R). Citrullination of tau impacts fibrillization and oligomerization rates in aggregation assays. Utilizing a panel of novel citrullinated tau (citR tau) antibodies, we identified citrullination of tau in vitro, several animal models of tauopathies, and Alzheimer's disease (AD). CitR tau increased with Braak stage and was enriched in AD brains with higher pathological tau burden. This work provides a new area of tau biology that signifies further consideration in the emerging spectrum of tauopathies and its clinical understanding.
    Keywords:  Citrullination; Peptidyl arginine deiminases (PADs); Posttranslational modifications; Tau; Tauopathy; citR antibodies
    DOI:  https://doi.org/10.1007/s00401-025-02965-5
  22. Nat Commun. 2025 Dec 02. 16(1): 10846
    Aberrant neural activity in the peritumoral cortex underlies the progression of tumor-associated seizures.
    Bibi L J Bouwen, Anne Bolleboom, Yuanhong Tang, Zhaofei Yu, Anna van der Stap, Jort A van Rij, Vera van Dis, Clemens M F Dirven, Chris I De Zeeuw, Olaf van Tellingen, Jian K Liu, Arnaud J P E Vincent, Zhenyu Gao.
      Seizures are frequent complications in brain tumor patients, yet the underlying neuronal mechanisms remain poorly defined. Here, we examined pathophysiological alterations in the peritumoral cortex of patients undergoing tumor resection. The synaptic activity, dendritic spine density, and gene expression of peritumoral pyramidal neurons differed significantly between patients with and without seizures. Using an inducible glioma rodent model, we characterized the progression of these alterations and their predictive value for seizure initiation. Computational simulations revealed that human cortical neurons are highly susceptible to synaptic and dendritic perturbations, which induce paroxysmal depolarizing shifts (PDS) in affected networks. Longitudinal analyses post-surgery showed that PDS were detectable prior to seizure onset in a subset of patients and reliably predicted post-resection seizure occurrence. These findings elucidate key neuronal substrates of tumor-associated seizures and suggest PDS as a potential biomarker for seizure risk, offering a foundation for targeted diagnostic and therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-025-66226-5
  23. Nat Commun. 2025 Dec 01. 16(1): 10817
    Dietary lipid content modifies wah-1/AIFM1-associated phenotypes via LRK-1 and DRP-1 expression in C. elegans.
    Mrityunjoy Mondal, Enzo Scifo, Rossella Erminia Ciliberti, Lena Wischhof, Tannaz Norizadeh Abbariki, Joshua Jackson, Ioanna-Maria Menegatou, Viktoria Zeisler-Diehl, Jan Riemer, Benjamin Jussila, Christopher E Hopkins, Sylwia Kierszniowska, Lukas Schreiber, Pierluigi Nicotera, Dan Ehninger, Daniele Bano.
      Eukaryotic cells rely on mitochondria to fine-tune their metabolism in response to environmental and nutritional changes. However, how mitochondria adapt to nutrient availability and how diets impact mitochondrial disease progression, remain unclear. Here, we show that lipid-derived diets influence the survival of Caenorhabditis elegans carrying a hypomorphic wah-1/AIFM1 mutation that compromises mitochondrial Complex I assembly. Comparative proteomic and lipidomic analyses reveal that the overall metabolic profile of wah-1/AIFM1 mutants varies with bacterial diet. Specifically, high-lipid diets extend lifespan by promoting mitochondrial network maintenance and lipid accumulation, whereas low-lipid diets shorten animal survival via overactivation of LRK-1 and DRP-1. We demonstrate that LRK-1 inhibition downregulates DRP-1 expression, reduces mitochondrial network fragmentation, and attenuates excessive autophagy, thereby rescuing the survival defects of wah-1 mutants maintained on low-lipid diets. Together, these findings suggest that nutrition, and particularly lipid intake, may ameliorate certain disease phenotypes associated with an inherited mutation that disrupts mitochondrial bioenergetics.
    DOI:  https://doi.org/10.1038/s41467-025-66900-8
  24. J Neuroinflammation. 2025 Dec 03.
    High throughput identification of genetic regulators of microglial inflammatory processes in Alzheimer's disease.
    Christopher L Cardona, Lai Wei, Joonwon Kim, Ellen Angeles, Gunjandeep Singh, Shiye Chen, Ronak Patel, Nkechime Ifediora, Peter Canoll, Andrew F Teich, Gunnar Hargus, Alejandro Chavez, Andrew A Sproul.
      
    Keywords:  Alzheimer’s disease; CRISPRi screen; CROP-seq; EED; INPP5D; Inflammation; MS4A6A; Microglia; RABEP1; hiPSCs
    DOI:  https://doi.org/10.1186/s12974-025-03562-9
  25. Immunobiology. 2025 Dec 02. pii: S0171-2985(25)00279-7. [Epub ahead of print]230(6): 153145
    Copper regulates the expression of immune genes in microglial cells in vitro.
    Laura Craciun, Sandra E Muroy, Kaoru Saijo.
      Copper, a transition metal, plays crucial roles in various physiological functions, including those of the nervous and immune systems. Dysregulation of copper homeostasis is linked to several diseases, such as neurodegenerative diseases. Since dysfunctional microglial immunity can also contribute to such diseases, we investigated the role of copper in microglial immunity. Currently, the roles of copper in microglial immunity are considered complex and multifaceted, with both anti- and pro-inflammatory effects having been proposed. In the current study, we found that both increased and decreased copper levels suppressed lipopolysaccharide (LPS)-mediated inflammation in microglial cells, as determined by RT-qPCR analysis. RNA sequencing (RNA-seq) analysis confirmed that increased copper levels reduced the inflammatory response to LPS; however, it also showed that decreased copper levels affected genes involved in cell proliferation, transcription, and autophagosome regulation. These findings suggest that copper is vital for maintaining normal immune functions in microglia, and that both copper excess and deficiency can disrupt microglial immunity.
    Keywords:  Copper; Gene expression analysis; Immunity; Microglia
    DOI:  https://doi.org/10.1016/j.imbio.2025.153145
  26. Acta Neuropathol. 2025 Dec 03. 150(1): 60
    Nucleolar aggregation of key neuropathological proteins in the postmortem neurodegenerative brain.
    Guinevere F Lourenco, Maria Elizabeth Torres-Pacheco, YuHong Fu, Hongyun Li, Heather McCann, Claire E Shepherd, Jillian J Kril, Glenda M Halliday.
      Nucleolar disturbances have long been implicated in neurodegenerative diseases but, to date, aggregation and immobilization of proteins into nucleolar bodies have only been reported in vitro and in cell models, and only for amyloid β (Aβ). In model systems, these bodies have been shown to coordinate local nuclear protein synthesis with potential to seed diagnostic neuropathologies. Here we confirm the presence of nucleolar aggregates of amyloid nature in postmortem brain tissue from controls and patients with neurodegenerative pathologies and demonstrate the nucleolar sequestration of fibrillation-prone proteins associated with neurodegenerative diseases (Aβ, tau, α-synuclein, TDP-43, and FUS, but not prion or peptide repeats). We identified nucleolar bodies ranging from multiple small foci to a centralized, large amyloid aggresome, that appear to represent progressive stages of protein immobilization from liquid-like foci to the formation of nucleolar aggresomes. Neurons with nucleolar aggresomes were more vulnerable to neurodegeneration, decreasing in number with increasing duration of disease. Nucleolar aggresomes with phosphorylated tau correlated with increasing amounts of neuropathology, while phosphorylated TDP-43 in nucleolar aggresomes distinguished cases with limbic-predominant age-related TDP-43 encephalopathy. Nucleolar aggresomes containing α-synuclein occurred in a large proportion of aged controls with limited neuronal loss (potentially asserting neuroprotection). Other fibrillation-prone proteins were either absent (prion and peptide repeats) or found less commonly in nucleolar aggresomes (Aβ and FUS), and amyloidogenic nuclear proteins not screened in this study may also occur in nucleolar aggresomes. Our data do not support the concept that proteins in aggresomes seed diagnostic neuropathologies as there were no associations between their presence in nucleoli aggresomes and their cytoplasmic or extracellular accumulation. Assessment of neurons with and without phosphorylated tau or α-synuclein aggresomes showed that phosphorylated tau ameliorated the increased DNA levels found in AD. Collectively, our observations establish that nucleolar sequestration of amyloidogenic proteins is a common molecular mechanism in the brain, representing a novel contribution to the understanding of nucleolar protein aggregation in the context of neuroprotection and neurodegeneration during brain aging.
    Keywords:  Neurodegeneration; Nucleolar aggregation; Nucleolar aggresomes; Nucleolar amyloid bodies; Nucleolar cavities; Nucleolar sequestration; Nucleolus
    DOI:  https://doi.org/10.1007/s00401-025-02968-2
  27. Nat Commun. 2025 Dec 03. 16(1): 10604
    Laminar organization of pyramidal neuron cell types defines distinct CA1 hippocampal subregions.
    Maricarmen Pachicano, Shrey Mehta, Angela Hurtado, Tyler Ard, Jim Stanis, Bayla Breningstall, Michael S Bienkowski.
      Investigating the cell type organization of hippocampal CA1 is essential for understanding its role in memory and cognition and its susceptibility to neurological disorders like Alzheimer's disease and epilepsy. Multiple studies have identified different organizational principles for gene expression and how it reflects cell types within the CA1 pyramidal layer including gradients or mosaic. Here, we identify sublaminar gene expression patterns within the mouse CA1 pyramidal layer that span across the entire hippocampal axis. Our findings reveal that CA1 subregions (CA1d, CA1i, CA1v, CA1vv) contain differentially distributed layers of constituent cell types and can be identified by regional gene expression signatures. This work offers a new perspective on the organization of CA1 cell types that can be used to further explore hippocampal cell types across species.
    DOI:  https://doi.org/10.1038/s41467-025-66613-y
  28. Mol Neurobiol. 2025 Dec 06. 63(1): 266
    Leucine-Rich Repeat Kinase 2 Relates to Neuroaxonal Degeneration via Tau Pathology and Microglial Activation in Alzheimer's Disease.
    Alzheimer’s Disease Neuroimaging Initiative
      Leucine-rich repeat kinase 2 (LRRK2), a key contributor to Parkinson's disease (PD). However, its potential role in Alzheimer's disease (AD) progression remains unclear. This study analyzed baseline and 5-year follow-up data from 716 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 87 participants in the Parkinson's Progression Markers Initiative (PPMI). Participants had cerebrospinal fluid (CSF) LRRK2 or LRRK2 (rs34637584 and rs76904798) genotypes, CSF biomarkers for AD core pathology, microglial activation and synaptic function, and underwent cognitive assessments. The mean age was 72.62 ± 7.34 years for the ADNI and 62.32 ± 9.66 years for the PPMI. The associations between LRRK2 and AD biomarkers were tested in CN, MCI and AD groups. In both ADNI and PPMI, CSF LRRK2 levels were correlated with CSF P-tau, T-tau, NfL, and α-syn. In ADNI, CSF LRRK2 showed correlations with sTREM2, PGRN, TREM2, TREML2, TRML1.ITIM, and Ng. Longitudinally, CSF LRRK2 was only correlated with the MOCA score in PPMI. Across CN, MCI, and AD groups, CSF LRRK2 levels exhibited correlations with sTREM2, PGRN, TREM2, TREML2, TREML1.ITIM, and NfL. The association between CSF LRRK2 and T-tau and P-tau was most pronounced in the MCI stage. Conversely, no significant association was observed between CSF LRRK2 and Aβ42 levels. Additionally, significant indirect effects were found in the TREM2-dependent mediation pathway in ADNI. This study suggests that CSF LRRK2 promotes tau-associated synaptic neurodegeneration, and TREM2-related microglial activation may play an important role.
    Keywords:  Alzheimer’s disease; LRRK2; Microglia; Neurodegeneration; Tau pathology
    DOI:  https://doi.org/10.1007/s12035-025-05580-3
  29. Glia. 2026 Feb;74(2): e70104
    Altered Mechanical Properties of Astrocytes Lacking MLC1: Implications for the Leukodystrophy MLC.
    Quinty Bisseling, Emma M J Passchier, Freya M Kirwan, Nelda Antonovaite, Serena Camerini, Maria S Brignone, Amélie Freal, Huibert D Mansvelder, Elena Ambrosini, Marjo S van der Knaap, Rogier Min.
      Loss of function of the astrocyte protein MLC1 causes Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC), a leukodystrophy characterized by white matter edema and slow neurological deterioration. MLC1 dysfunction leads to swelling of perivascular astrocyte endfeet and an impaired attachment of endfeet to blood vessels. In isolated primary astrocytes, loss of MLC1 hinders recovery of astrocytes from cell swelling, but the cellular function of MLC1 is not completely understood. MLC1 modulates gating of mechanosensitive ion channels involved in volume regulation. The cytoskeleton plays a crucial role in cell volume regulation, and interactions between the cytoskeleton and cell membrane affect the properties of mechanosensitive ion channels. Therefore, we investigated whether primary Mlc1-null mouse astrocytes show a disruption in their mechanical properties. We measured the mechanical properties of cultured primary astrocytes with an indentation technique and demonstrated that Mlc1-null astrocytes are softer than wild-type astrocytes. Proteomic analysis and western blots confirmed dysregulation of several cytoskeleton-related pathways in Mlc1-null astrocytes. Confocal imaging revealed that the organization of the actin cytoskeleton and microtubule acetylation are unaffected. Instead, in Mlc1-null astrocytes we observed a decrease in the number of focal adhesions, which aid in relaying mechanical forces between the cytoskeleton, cell membrane, and the extracellular matrix (ECM). Inversely, overexpression of MLC1 in HeLa cells led to an increase in focal adhesions. Together, our findings reveal that the mechanical properties of Mlc1-null astrocytes are altered, and that disrupted cytoskeleton-membrane-ECM interactions potentially play a role in the disease. Modulators of astrocyte mechanobiology might therefore hold promise for MLC therapy development.
    Keywords:  astrocyte; cytoskeleton; focal adhesions; leukodystrophy; mechanobiology
    DOI:  https://doi.org/10.1002/glia.70104
  30. Nat Commun. 2025 Dec 03. 16(1): 10866
    APIP regulates the priming of canonical NLRP3 and non-canonical Caspase-11/4 inflammasomes by binding to TRAF6.
    Kwangmin Jung, Meiko Kawamura, Bitna Lim, Manabu Abe, Kenji Sakimura, Masaaki Komatsu, Yong-Keun Jung.
      Apaf-1-interacting protein (APIP) has been implicated in inflammation-related processes, including myocardial infarction and cancer progression. However, its role in systemic inflammation remains elusive. Here, we investigate the APIP-mediated regulation of inflammasome activity in mice and human macrophages. Loss of APIP in the myeloid lineage (Apip cKO mice) compromises the activation of canonical NLRP3 and non-canonical caspase-11 inflammasomes, reducing pyroptosis in bone marrow-derived macrophages (BMDM). Conversely, these inflammatory responses are enhanced in BMDMs from APIP-transgenic mice. Consistently, APIP knockdown in human macrophages inhibits the activation of NLRP3 and caspase-4 inflammasomes. Mechanistically, APIP binds to TRAF6, activating downstream NF-κB and JNK signaling and facilitating the priming of both inflammasomes. Importantly, systemic inflammation induced by LPS or bacterial infection is attenuated in Apip cKO mice but exacerbated in APIP-transgenic mice. Thus, our findings suggest that APIP is crucial in regulating both canonical and non-canonical inflammasomes, presenting a potential therapeutic target for inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41467-025-65893-8
  31. Glia. 2026 Feb;74(2): e70108
    NG2-Glia Heterogeneity Across Cortical Layers.
    Sonsoles Barriola, Lina María Delgado-García, Ana Cristina Ojalvo-Sanz, Carolina Pernia-Solanilla, María Figueres-Oñate, Laura López-Mascaraque.
      NG2-glia are a unique and heterogeneous glial cell population with diverse roles in the central nervous system. However, their morphological diversity across brain regions and cortical layers remains poorly understood. Here, we use StarTrack labeling and in utero electroporation at embryonic day 14 (E14) to reconstruct individual NG2-glial cells in the adult mouse cortex and corpus callosum. Through detailed two- and three-dimensional morphometric analyses, including Sholl analysis, principal component analysis (PCA), and hierarchical clustering, we uncover striking layer-specific patterns. NG2-glia in deep cortical layers (L5-6) exhibit significantly larger somatic areas, more elaborate arborizations, and higher process complexity compared to those in superficial layers (L1-4) and the corpus callosum. In contrast, NG2-glia in layer 1 and the corpus callosum share a compact morphology characterized by smaller somata and simplified processes, suggesting common microenvironmental constraints. Moreover, Sholl analysis, PCA, and hierarchical clustering reveal distinct morphological subpopulations within the NG2-glial population and highlight heterogeneity in upper cortical layers. Comparative analyses with astrocytes reveal fundamental structural differences: NG2-glia have thinner, longer processes and larger enclosing radii but occupy smaller volumes, whereas astrocytes form denser, more compact arbors with higher branch numbers. Together, our findings establish the first comprehensive morphological atlas of cortical adult NG2-glia, highlighting region- and layer-specific adaptations that likely underlie their diverse roles in CNS physiology and repair.
    Keywords:  StarTrack labeling; astrocyte comparison; cortical layering; glial diversity; morphometric analysis; synaptic interaction
    DOI:  https://doi.org/10.1002/glia.70108
  32. Nat Commun. 2025 Dec 03. 16(1): 10850
    A distinct PP2A subunit regulates local protein phosphorylation at the axon initial segment.
    Andrew P Anderson, Sanghyun Kim, Allison J Melton, Xiaoyun Ding, Wei Zhang, Alexander B Saltzman, Anna Malovannaya, Matthew N Rasband, Yudong Gao.
      Protein phosphorylation plays a crucial role in regulating the cytoskeletal and membrane proteins at the axon initial segment (AIS). However, our knowledge of AIS-specific kinases and phosphatases is very limited. Here, we report the identification of a protein phosphatase 2A (PP2A) B55 regulatory subunit enriched at the AIS in mice: Ppp2r2c. Our results demonstrate that PP2A-B55 subunits exhibit substantial heterogeneity in their subcellular localization and function. Notably, the Ppp2r2c subunit is selectively concentrated at the AIS, and this enrichment is driven by its unique structure. Utilizing a microelectrode array system (MEA), we show that Ppp2r2c modulates neuronal activity during in vitro development. With phosphoproteomics, we further reveal that the potassium channel Kv1.2 is one of the downstream targets that link Ppp2r2c activity to neuronal excitability. Together, these data provide a critical entry point for understanding the mechanisms of PP2A-mediated local phospho-regulation at the AIS.
    DOI:  https://doi.org/10.1038/s41467-025-66120-0
  33. Mol Neurobiol. 2025 Dec 01. 63(1): 233
    Chronic Styrene Exposure Causes Oxidative Stress, Neuroinflammation, and Hippocampal Memory Dysfunction via NLRP3 Inflammasome Activation.
    Raffaele Montuoro, Anna Pisani, Veronica Mohamed Hizam, Claudia Vernamonte, Giammarco Boni, Jacopo Galli, Renata Sisto, Fabiola Paciello, Anna Rita Fetoni, Claudio Grassi.
      Several studies focused on the molecular mechanisms linking oxidative stress and inflammation, due to their crucial role in different pathological conditions, including neurodegenerative disorders. Here, we studied the link between redox unbalance and neuroinflammation in a model of styrene-induced toxicity in the hippocampus. We used a rat model of chronic styrene exposure to assess its impact on hippocampal function. Behavioral tests were performed to evaluate recognition and spatial memory. Molecular and histological analyses were carried out to measure ROS production, inflammatory markers (COX-2, TNF-α, IL-1β), and immunoreactivity for IBA-1 and GFAP. Synaptic alterations, activation of pro-apoptotic pathways, and NLRP3 inflammasome levels were also evaluated. We found that toxic exposure to styrene can affect both recognition and spatial memory by causing functional, morphological, and molecular alterations in the hippocampus. Indeed, we observed increased ROS production and elevated levels of inflammatory markers, as well as increased IBA-1 and GFAP immunoreactivity, suggesting an activation of the immune system with the involvement of microglia and astrocytes in the hippocampus of styrene-treated animals. These findings were associated with molecular and structural synaptic alterations and activation of pro-apoptotic pathways. Moreover, we pointed out the possible involvement of inflammasome activation in mediating oxidative-inflammatory damage, and we documented an increased level of NLRP3 inflammasome after styrene exposure. Our data provide novel experimental evidence of styrene-induced memory dysfunctions, demonstrating that exposure to this toxic compound can impinge on the hippocampus through a mechanism involving the ROS-driven inflammation, activating the NLRP3 inflammasome axis. From a translation point of view, our results indicate that styrene exposure can be a high-risk factor for developing cognitive deficits and suggest considering the ROS/NLRP3 pathway as a target to prevent/attenuate neurotoxicity.
    Keywords:  Cognitive decline; Inflammation; Microglia activation; Neurotoxicity; Oxidative stress; Synaptic dysfunctions
    DOI:  https://doi.org/10.1007/s12035-025-05472-6
  34. Nat Commun. 2025 Dec 03.
    Longitudinal proteomic profiling of cerebrospinal fluid in untreated multiple sclerosis defines evolving disease biology.
    Peter Kosa, Shinji Ashida, Keith Lumbard, Jing Wang, C Jason Liang, Ruturaj Masvekar, Yujin Kim, Mihael Varosanec, Lori Jennings, Bibiana Bielekova.
      Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, but the molecular mechanisms underlying its course remain incompletely understood. We measured 4789 cerebrospinal fluid proteins in 1040 samples from 438 individuals with MS and controls followed longitudinally. To isolate disease-related biology, we adjusted for normal aging, sex, while also measuring residual effects of demographic and genetic covariates. Here we show that 3714 proteins are significantly associated with twelve clinical and imaging outcomes, highlighting processes linked to viral infection, disruption of epithelial barriers, stromal cell-mediated tissue remodeling, demyelination, and synaptic and neuronal loss. We also find strong sex-related differences: men show greater activation of pathways associated with tissue injury and disability accumulation, whereas women upregulate neurodevelopmental programs that may promote resilience or repair. These molecular maps of MS natural history provide a framework for understanding disease mechanisms and a resource for future drug development.
    DOI:  https://doi.org/10.1038/s41467-025-65154-8
  35. Glia. 2026 Feb;74(2): e70103
    Astrocytic TCF7L2 Impacts Brain Osmoregulation and Restricts Neuronal Excitability.
    Mariusz Popek, Krzysztof Goryca, Dorota Adamska, Joanna Urban-Ciećko, Katarzyna Hryniewiecka, Marcin Lipiec, Tomasz Grzegorz Krawczyk, Kamil Rafalko, Alicja Ławicka, Shane A Liddelow, Lukasz Mateusz Szewczyk.
      Astrocytes differentiate and mature during postnatal development, but the molecular mechanisms linking their maturation to neuronal function remain unclear. We investigated the role of Wnt/β-catenin signaling and its effector, the transcription factor TCF7L2, in postnatal astrocytes using single-nucleus RNA sequencing, imaging, morphometric analysis, microdialysis, and electrophysiology in Tcf7l2 conditional knockout (cKO) mice. Loss of Tcf7l2 caused widespread transcriptional dysregulation in astrocytes, particularly in genes related to amino acid and ion transport, as well as membrane potential regulation. These mice showed disrupted amino acid homeostasis, astrocyte swelling, and impaired extracellular potassium clearance in the somatosensory cortex. These astrocytic changes were accompanied by altered gene expression in cortical pyramidal neurons, reduced excitability, and a hyperpolarized resting membrane potential. Our results suggest that astrocytic TCF7L2 is crucial in coordinating ion and amino acid transport in adulthood, thereby contributing to maintaining extracellular homeostasis and supporting neuronal function. This study identifies TCF7L2 as a key regulator of astrocyte-mediated neurophysiological support and underscores the importance of its role in astrocyte maturation during postnatal development.
    Keywords:  TCF7L2; Wnt/β‐catenin; astrocyte; neuron; transcription factor
    DOI:  https://doi.org/10.1002/glia.70103
  36. Nat Commun. 2025 Dec 05. 16(1): 10612
    Human oligodendrocyte progenitor cells mediate synapse elimination through TAM receptor activation.
    Asimenia Gkogka, Susmita Malwade, Marja Koskuvi, Sohvi Ohtonen, Ellinor Molnar, Raj Bose, Sandra Ceccatelli, Jari Koistinaho, Jari Tiihonen, Martin Schalling, Samudyata Samudyata, Carl M Sellgren.
      Oligodendrocyte progenitor cells (OPCs) have been implicated in synaptic remodelling in animal models, but the underlying mechanisms and their relevance to human brain development remain unclear. Here, we generate a human multi-lineage forebrain organoid model in which OPCs, together with microglia, form close contacts with synapses and spontaneously internalize synaptic material. Single-nucleus transcriptomic profiling with unbiased cell-cell communication analysis identifies the growth arrest-specific gene 6 (GAS6)-TYRO3, AXL, and MERTK (TAM) receptor axis as a key signalling pathway, with neurons and microglia expressing GAS6 and a subset of OPCs expressing AXL. Further, dose-dependent pharmacological inhibition of TAM receptors demonstrates the importance of AXL, and targeted reduction of AXL expression in OPCs impairs synaptic uptake. These findings reveal a role for GAS6-AXL signalling in driving synaptic internalisation by AXL+ OPCs during early human brain development.
    DOI:  https://doi.org/10.1038/s41467-025-66521-1
  37. Brain Pathol. 2025 Dec 04. e70056
    Tau-targeting active immunotherapy slows progression and reduces pathology in mouse models of tauopathy.
    Christopher M Brown, Jeanne K Brooks, Louise Kelly, Madeline M Vroom, Matthew Longo, Jean-Cosme Dodart, Roxana Carare, Justin D Boyd.
      A novel class of active immunotherapy, consisting of proprietary T-helper peptide linked to a B-cell epitope, is being developed to target tau in Alzheimer's disease (AD). These experimental therapies generate antibodies that have demonstrated binding to pathological tau in vitro, and efficacy in cell-based tau aggregation assays comparable to monoclonal antibodies. Here, we report the ability of one such tau-targeting immunotherapy, p5555kb, to prevent the progression of tau pathology using two distinct mouse models. P301L mice were immunized with p5555kb and showed greater survival rates at 210 days than saline-inoculated control mice. The efficacy of p5555kb against tau seeding in vivo was assessed by injecting C57BL6 mice with tau fibrils purified from post-mortem human AD brain tissue. Immunization with p5555kb significantly reduced the amount of tau inclusions detected by immunohistochemistry at 9 months post-injection, as compared to saline inoculation. This study demonstrates that p5555kb is effective at inducing functional tau-targeting antibodies, which prevented the onset of adverse phenotypes associated with tau pathology in vitro and in vivo.
    Keywords:  Alzheimer's disease; active immunotherapy; tau; tau seeding; tauopathy
    DOI:  https://doi.org/10.1111/bpa.70056
  38. J Neuroinflammation. 2025 Dec 04.
    SerpinA3N-APOE interaction in astrocytes exacerbates Alzheimer's disease progression through NFκB activation.
    Chenming Liu, Sutong Xu, Hongkai Yao, Yali Wang, Qiulu Liu, Haiyue Zhou, Yuping Luo, Xuekun Li, Siguang Li, Chun Li.
      Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by β-amyloid (Aβ) deposition, neurofibrillary tangles, neuronal loss, and neuroinflammation. It represents a growing global health crisis. Although astrocytes contribute to neuroinflammatory cascades, their molecular regulators in AD progression remains elusive. Here, through single-cell transcriptomic analysis, we identified SerpinA3N as a disease-progressive modulator upregulated in AD astrocytes, with expression levels correlating with pathological severity. Astrocytic SerpinA3N knockdown in AD mice rescued cognitive deficits across multiple behavioral tests, and concurrently attenuated neuroinflammatory responses, as evidenced by decreased astrocytic/microglial activation and reduced cytotoxic substance release. Moreover, histopathological analyses demonstrated decreased neuronal loss and Aβ deposition following SerpinA3N knockdown. Mechanistically, we elucidated that SerpinA3N cooperated with APOE to exacerbate AD pathology through NFκB signaling activation. Our study uncovers a novel astrocyte-mediated pathogenic cascade driving AD progression and establishes SerpinA3N as a promising therapeutic target for neuroinflammation modulation in AD.
    Keywords:  APOE; Alzheimer's disease; Astrocytes; NFκB signaling pathway; Neuroinflammation; SerpinA3N
    DOI:  https://doi.org/10.1186/s12974-025-03644-8
  39. Alzheimers Res Ther. 2025 Nov 29.
    Single-cell analysis reveals shared and distinct molecular signatures in brain organoid models of neurodegeneration and neuroinflammation.
    Sophie Le Bars, Mohamed Soudy, Sarah Louise Nickels, Jens Christian Schwamborn, Enrico Glaab.
      
    Keywords:  Alzheimer's disease; Brain organoids; Cell-cell communication; Comparative transcriptomics; Neurodegeneration; Parkinson's disease; Single-cell transcriptomics; Systems biology
    DOI:  https://doi.org/10.1186/s13195-025-01926-0
  40. J Gen Virol. 2025 Dec;106(12):
    Extracellular vesicles released from Marek's disease virus-transformed T-cells impact immune cell proliferation.
    Laëtitia Trapp-Fragnet, Julien Burgaud-Gaillard, Valérie Labas, Sylvie Rémy, Ana-Paula Texeira-Gomes, Caroline Denesvre.
      Marek's disease virus (MDV) is an alphaherpesvirus responsible for the development of T-cell lymphoma in chickens. Despite the identification of several pro-oncogenic viral molecules encoded by MDV, the processes leading to tumourigenesis remain poorly understood. Extracellular vesicles (EVs) are important mediators of intercellular communication, carrying bioactive molecules that can elicit profound physiological changes in recipient cells. Tumour cells can release significant amounts of EVs, which influence tumour development and growth, metastatic processes and resistance to cancer therapies. These EVs favour cancer cells to evade the immune response, particularly by establishing an immunosuppressive microenvironment. Here, we investigated whether EVs produced by MDV-transformed T lymphocytes affect the proliferation of avian immune cells, a determining feature in neoplastic processes. EVs were purified from an MDV-transformed cell line cultured in vitro. Using a proteomic approach, we confirmed the presence of specific markers and identified a panel of cellular proteins enriched in these EVs. Notably, no viral proteins were detected in the purified EVs. We also demonstrated that EVs are rapidly internalized by recipient chicken cells. Moreover, these EVs can induce a decrease in primary chicken B-cell proliferation, while promoting primary chicken T-cell proliferation. Our findings suggest that EVs released by MDV-transformed cells may contribute to immunosuppression and potentially facilitate lymphoma progression by enhancing T-cell proliferation.
    Keywords:  Marek’s disease virus; chicken lymphocytes; exosome; extracellular vesicles; lymphomagenesis; proliferation
    DOI:  https://doi.org/10.1099/jgv.0.002191
  41. Funct Integr Genomics. 2025 Dec 06. 25(1): 266
    Transcriptome analysis reveals reduced lipid accumulation and mitochondrial metabolic remodeling in ADCY3-overexpressing adipocytes.
    Lu Liu, Houxue Cui, Zhongfang Xiang, Nanxi Dong, Dong Niu.
      Excessive adipose tissue accumulation adversely impacts the health of both humans and livestock. Adenylyl cyclase 3 (ADCY3) is a promising anti-obesity target, yet its regulatory role in adipogenesis remains incompletely understood. Our findings revealed a dynamic pattern of ADCY3 expression during adipogenesis and lipid droplet (LDs) accumulation. Functional analyses demonstrated that ADCY3 overexpression impaired adipogenesis by downregulating adipogenic transcription factors CEBPα and PPARγ. Furthermore, it reduced both the number and size of LDs through suppressing triglyceride synthesis and fatty acid metabolism, concomitantly downregulating key genes involved in LDs formation (PLIN1, CIDEC, FIT2, and Seipin), as well as factors mediating glycerol ester synthesis and fatty acid metabolism (DGAT1, DGAT2, ACC, SCD, FASN, and ACSL1). Transcriptomic profiling revealed that ADCY3 overexpression suppressed PPARγ signaling, leading to the downregulation of oxidative phosphorylation genes encoded by both the nuclear and mitochondrial genomes. Our results implicate ADCY3 in the regulation of lipid metabolism, with the speculative involvement of mitochondrial metabolic remodeling. This perspective offers a framework for developing future interventions against excessive lipid deposition.
    Keywords:  Lipid metabolism ADCY3 adipocyte transcriptome mitochondrion
    DOI:  https://doi.org/10.1007/s10142-025-01789-6
  42. Commun Biol. 2025 Dec 04. 8(1): 1745
    Astrocyte activation persists one year after TBI: a dynamic shift from inflammation to neurodegeneration.
    Hadi Abou-El-Hassan, Taha Yahya, Benjamin E Zusman, Omar Albastaki, Harm T Imkamp, Jessica J Ye, Francesca Percopo, Jonathan R Christenson, Maryam H Al Mansi, Kuan-Jung Lu, Galina Gabriely, Bruna K Tatematsu, Karl J Habashy, Juliana R Lopes, Amir-Hadi Maghzi, Rafael M Rezende, Francisco J Quintana, Howard L Weiner, Saef Izzy.
      Traumatic brain injury (TBI) remains a leading cause of chronic neurological impairment, yet the cellular mechanisms underlying long-term neurodegeneration in TBI remain incompletely understood. Astrocytes, the most abundant glial cell type, are central to maintaining neuroglial and neurovascular homeostasis. Following TBI, however, astrocytic activation contributes to sustained inflammation and neurotoxicity. In this study, we employed immunohistochemistry and RNA sequencing to longitudinally profile astrocyte morphology and transcriptional states at acute (2 days), subacute (2 weeks), and chronic (1 year) stages after controlled cortical impact in mice. We identified a temporally evolving astrocyte response-beginning with a pro-inflammatory profile acutely, transitioning through a profile suggestive of mixed inflammatory and neurodegenerative signatures subacutely, and culminating in a chronic state marked generally by expression of Alzheimer's and Parkinson's disease-associated genes. Notably, a subset of astrocyte-derived progenitor cells also was found up to one-year post-injury, expressing markers associated with neurogenesis. These findings reveal that astrocyte activation is not transient but persists chronically, undergoing a dynamic shift from inflammation to degeneration. The observed parallels between astrocyte states in chronic TBI and neurodegenerative disorders underscore their potential role in post-traumatic cognitive decline and highlight astrocyte-targeted interventions as a promising avenue for therapeutic development.
    DOI:  https://doi.org/10.1038/s42003-025-09138-w
  43. Mol Neurobiol. 2025 Dec 01. 63(1): 231
    Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Alzheimer's Disease: Recent Advances and Controversies.
    Lingling Zhang, Li Zhang, Junjie Zhao, Wei Zhang, Hao Zhang.
      Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by the gradual deterioration of memory, imposes a significant global socioeconomic burden. Despite mechanistic insights into amyloid-β (Aβ) and tau pathways, effective therapies remain elusive. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol metabolism, has emerged as a multifunctional player in neurodegenerative processes. Initially studied for its role in cardiovascular health, recent evidence implicates PCSK9 in AD pathogenesis through mechanisms involving Aβ clearance, neuroinflammation, and receptor-mediated cholesterol trafficking. However, conflicting genetic and clinical data complicate its therapeutic potential. This review synthesizes current knowledge on PCSK9's role in AD, highlighting molecular pathways, clinical controversies, and implications for therapeutic development. Resolving these complexities could advance targeted diagnostics and disease-modifying therapies.
    Keywords:  Alzheimer’s disease; Amyloid-β; Cholesterol metabolism; Neuroinflammation; PCSK9; Therapy
    DOI:  https://doi.org/10.1007/s12035-025-05424-0
  44. Nat Commun. 2025 Dec 04. 16(1): 10898
    Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.
    Tatiana N Tarasenko, Emily Warren, Bharati Singh, Amanda Fuchs, Jose Marin, Marten Szibor, Christopher King, Peter J McGuire.
      T cell activation requires extensive metabolic reprogramming, but the specific requirement for mitochondrial respiration (MR) remains unresolved. While most studies have focused on aerobic glycolysis as the primary driver of proliferation and effector function, the role of MR has not been completely defined. To isolate MR from proton pumping by cytochrome c oxidase (COX), we expressed the non-proton-pumping alternative oxidase (AOX) in activated COX-deficient T cells. AOX restored electron flow, membrane potential, and mitochondrial ATP production, ultimately rescuing proliferation, effector and memory differentiation, and antiviral immunity. These improvements required upstream electron input, particularly from Complex I, with Complex II and DHODH contributing more modestly. Despite restored MR, glycolysis remained elevated, likely due to altered redox signaling. These findings demonstrate that MR, normally mediated by COX, is necessary and can be sufficient to support T cell activation and function, independent of proton translocation, provided upstream electron input is maintained.
    DOI:  https://doi.org/10.1038/s41467-025-65910-w
  45. Nature. 2025 Dec;648(8092): 23-25
    The 'silent' brain cells that shape our behaviour, memory and health.
    Alison Abbott.
      
    Keywords:  Alzheimer's disease; Brain; Cell biology; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-03912-w
  46. J Alzheimers Dis. 2025 Dec 04. 13872877251400787
    Experiences of participant burden in an Alzheimer's disease research center longitudinal cohort.
    Theresa F Gierzynski, Jonathan M Reader, Bernardo Flores, Joshua T Fox-Fuller, Renee Gadwa, Arijit Bhaumik, Judith Heidebrink, Bruno Giordani, Benjamin M Hampstead, Kelly M Bakulski, Henry Paulson, J Scott Roberts, Annalise Rahman-Filipiak.
      BackgroundParticipant attrition can compromise the statistical power and generalizability of research results. Prior investigations have shown that perceptions of higher research burden are positively associated with participant withdrawal from longitudinal studies.ObjectiveWe measured participants' perceived burden in a cohort of older adult research participants enrolled in a longitudinal study of memory and aging at the Michigan Alzheimer's Disease Research Center (MADRC).MethodsParticipants completed a modified, 22-item version of the Perceived Research Burden Assessment (PeRBA), which quantitatively measures perceptions of research burden. We performed a multiple linear regression analysis to ascertain the associations between individual participant characteristics (e.g., demographic, clinical, and logistical/socioecological factors) and ratings of perceived research burden.ResultsA total of 300 participants completed the PeRBA. Overall burden was relatively low (mean = 36.6, SD = 9.38), with possible scores ranging from 22-110. Participants who self-identified as Black/African American reported significantly higher levels of perceived research burden relative to participants who self-identified as non-Hispanic White (β = 6.91, p < 0.001). Additionally, participants with a dementia diagnosis endorsed significantly higher levels of burden than their cognitively unimpaired counterparts (β = 4.85, p = 0.03). All other independent variables were not significantly associated with burden appraisal (p > 0.05).ConclusionsThe PeRBA is a useful tool for monitoring participant burden, as well as identifying differential levels of self-reported burden within research cohorts. These findings can inform tailored retention strategies that support the sustained engagement of participants, particularly those who may be the most susceptible to research burden.
    Keywords:  Alzheimer's disease; human subject research; longitudinal research; participant retention; research burden
    DOI:  https://doi.org/10.1177/13872877251400787
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