bims-micgli Biomed News
on Microglia
Issue of 2025–10–05
fourteen papers selected by
Matheus Garcia Fragas, Universidade de São Paulo
  1. Microglial ADGRG1: AD glial resilience generator.
  2. Microglial glycolytic reprogramming in alzheimer's disease: association with impaired phagocytic function and altered vascular proximity.
  3. Reversible tau hyperphosphorylation in hibernation: a blood biomarker and brain tissue study.
  4. Cerebrospinal fluid neuronal pentraxin levels are associated with tau pathology via microglia-astrocyte signaling in alzheimer's disease.
  5. Making tracks: microglia and the extracellular matrix.
  6. Intercellular communication in the brain through a dendritic nanotubular network.
  7. Cytokine expression profile in the human brain of older adults.
  8. Amyloid beta and tau are associated with the dual effect of neuroinflammation on neurodegeneration.
  9. Modular inflammation network discovery from large-scale phenotypic screening in genetically heterogeneous mouse brains.
  10. Blocking axon-glial mechanotransduction to prevent concussive brain injury.
  11. Decoding adipose-brain crosstalk: Distinct lipid cargo in human adipose-derived extracellular vesicles modulates amyloid aggregation in Alzheimer's disease.
  12. Munc13-1 restoration mitigates presynaptic pathology in spinal muscular atrophy.
  13. Decoding Alzheimer's disease at the cellular level reveals promising combination therapy.
  14. Integrative analysis reveals generalizable human neurodegenerative disease-associated glial states.
  1. Neuron. 2025 Oct 01. pii: S0896-6273(25)00669-5. [Epub ahead of print]113(19): 3070-3072
    Microglial ADGRG1: AD glial resilience generator.
    Kia M Barclay, Qingyun Li.
      Microglial states underlying Alzheimer's disease (AD) have been well characterized in animal models and human samples, yet their regulation remains elusive. In this issue of Neuron, Zhu et al.1 uncover Adgrg1, which governs a protective microglia phenotype through MYC activation.
    DOI:  https://doi.org/10.1016/j.neuron.2025.09.003
  2. J Neuroinflammation. 2025 Oct 02. 22(1): 223
    Microglial glycolytic reprogramming in alzheimer's disease: association with impaired phagocytic function and altered vascular proximity.
    Ning Lu, Zhongman Jin, Nian Liu, Caiyun Zhu, Hui Wei, Qi Xu.
       BACKGROUND: Alzheimer's disease (AD) is characterized by chronic neuroinflammation alongside amyloid-beta plaque and phosphorylated tau (p-Tau) tangle accumulation. Microglia, as resident immune cells, undergo glycolytic reprogramming that may exacerbate inflammation and impede toxic protein clearance. Specifically, the glycolytic enzyme pyruvate kinase M2 (PKM2) drives proinflammatory microglial phenotypes linked to neurodegeneration. This study investigates how PKM2-mediated microglial glycolytic reprogramming and inflammatory responses alongside Aβ/p-Tau clearance in human AD brains.
    METHODS AND RESULTS: Hippocampal-entorhinal cortex (HP-EC) tissues from 8 AD patients and 8 matched controls underwent multiplex immunohistochemistry and high-resolution spatial analysis. PKM2+Iba1+ microglia density significantly increased in AD versus controls (p < 0.001), predominantly displaying a disease-associated microglial (HAM-like) phenotype (ABCA7+) with concurrent lipid-droplet accumulation (PLIN3+; LDAM phenotype). Spatially, glycolytic PKM2+Iba1+ microglia accumulated near Aβ plaques, p-Tau tangles, and cerebral vasculature. Notably, their distribution around plaques/tau showed anomalous increasing density with distance (p < 0.001), suggesting impaired chemotaxis. Perivascular localization lacked clear chemotactic gradients. Functionally, overall phagocytic activity (CD68+) decreased significantly in AD (p = 0.001), primarily attributed to PKM2- subsets, whereas PKM2+Iba1+ microglia exhibited pronounced phagocytic exhaustion (PLIN2+; p < 0.001), consistent around both Aβ and p-Tau lesions (all p < 0.001).
    CONCLUSION: Our study establishes that microglial glycolytic reprogramming via PKM2 promotes a proinflammatory HAM-like phenotype, phagocytic exhaustion, and peri-pathological accumulation with aggregates and cerebral vessels. Targeting glycolytic pathways represents a viable therapeutic strategy for alleviating microglial dysfunction and neuroinflammation in AD.
    Keywords:  Alzheimer’s disease; Glycolysis; Microglia; Neuroinflammation; PKM2
    DOI:  https://doi.org/10.1186/s12974-025-03546-9
  3. Acta Neuropathol. 2025 Sep 29. 150(1): 36
    Reversible tau hyperphosphorylation in hibernation: a blood biomarker and brain tissue study.
    Wagner S Brum, Laia Montoliu-Gaya, Gunnar Brinkmalm, Diana Piotrowska, Elena Camporesi, Carsten Jäger, Helena S Isaksson, Sven Martin, Jonas Kindberg, Juan Lantero-Rodriguez, João Pedro Ferrari-Souza, Alexis Moscoso, Andrea L Benedet, Shorena Janelidze, Johan Gobom, Henrik Zetterberg, Oskar Hansson, Eduardo R Zimmer, Nicholas J Ashton, Thomas Arendt, Tammaryn Lashley, Jens T Stieler, Max Holzer, Ole Fröbert, Kaj Blennow.
      Tau hyperphosphorylation, a key neuropathological feature of tauopathies such as Alzheimer's disease (AD), also occurs physiologically during mammalian hibernation and is fully reversed upon arousal, offering a unique translational model to study tau metabolism. However, limited data exist on insoluble and soluble tau alterations during hibernation and on patterns of tau fragment concentrations in the hibernating mammalian brain. We quantified tau biomarkers in plasma samples from ten free-ranging brown bears (Ursus arctos), captured during both their active summer period and hibernation in the winter, using clinically validated immunoassays and immunoprecipitation mass spectrometry (IP-MS) techniques. We also analyzed brain tissue from ten golden Syrian hamsters (Mesocricetus auratus) subjected to induced torpor (hibernation) versus euthermic (non-hibernating) states by quantifying multiple phosphorylated and non-phosphorylated tau peptides with an IP-MS method previously applied in human brain tissue. In brown bears, plasma levels of phosphorylated tau (p-tau) biomarkers p-tau181 and p-tau217 significantly increased during hibernation compared to summer (median increases of 362% and 294% by IP-MS, respectively), with similar increases found with immunoassays. Additional plasma p-tau biomarkers associated with AD pathology, including p-tau205 and p-tau231, were also increased during bear hibernation. In hamster brains, p-tau217, and p-tau231 were similarly elevated during torpor, while tau fragments from the microtubule-binding region (MTBR), associated with tangle aggregation, were not increased. In contrast, brain tissue from n = 10 AD patients, analyzed with the same IP-MS method, exhibited striking increases in p-tau (~ 50,000% for p-tau217) and MTBR fragments (~ 20,000% for MTBR tau354-369) compared with n = 10 human controls. We show that hibernation-linked tau hyperphosphorylation involves some of the same phospho-sites altered in AD, but occurs without MTBR tau aggregation. This highlights hibernation as a reversible, non-pathological model to study tau biology and mechanisms underlying AD due to its reversibility and lack of tau aggregation despite hyperphosphorylation in key AD tau phospho-sites.
    Keywords:  Alzheimer’s disease; Hibernation; Neuropathology; Phosphorylated tau; Plasma biomarkers; Tau; Tauopathies
    DOI:  https://doi.org/10.1007/s00401-025-02930-2
  4. J Neuroinflammation. 2025 Oct 02. 22(1): 221
    Cerebrospinal fluid neuronal pentraxin levels are associated with tau pathology via microglia-astrocyte signaling in alzheimer's disease.
    Zihao Zhang, Xin Chen, Zehu Sheng, Na Jiang, Wen-Quan Zou.
       BACKGROUND: Recent studies have reported that Neuronal Pentraxin 2 (NPTX2), a synapse-associated protein, can significantly predict the progression of cognitive decline. However, the role of the NPTX protein family in the pathological progression of Alzheimer's Disease (AD) in humans remains unclear.
    METHODS: This study included 263 participants from the Alzheimer's Disease Neuroimaging Initiative, including cognitively normal, mild cognitive impairment, and AD individuals, with a mean age of 73.99 ± 7.43 years. Cerebrospinal fluid (CSF) NPTX proteins and Glial Fibrillary Acidic Protein (GFAP) were quantified by Mass spectrometry, Soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2) by a Meso Scale Discovery-based multiplex immunoassay, and amyloid-beta 42 (Aβ42), phosphorylated tau (P-tau), and total tau (T-tau) by Roche Elecsys immunoassays. We systematically evaluated the associations between NPTX proteins and baseline CSF AD biomarkers, as well as their relationships with longitudinal biomarker changes. Mediation models were applied to explore whether GFAP and sTREM2 mediate the associations between NPTX proteins and T-tau pathology. Additionally, subgroup analyses based on A/T/(N) classification were conducted to assess stage-specific effects, and sensitivity analyses were performed using 18 F-fluorodeoxyglucose Positron Emission Tomography in place of CSF AD biomarkers.
    RESULTS: We found that CSF NPTX proteins were significantly associated with CSF sTREM2 (βNPTX1 = 0.293, p < 0.001; βNPTX2 = 0.387, p < 0.001; βNPR = 0.382, p < 0.001), GFAP (βNPTX1 = 0.274, p < 0.001; βNPTX2 = 0.472, p < 0.001; βNPR = 0.444, p < 0.001), and core AD biomarkers at baseline. The association between NPTX2 and T-tau levels was significant and independent of Aβ42 (β = 0.619, p < 0.001). Mediation analyses indicated that sTREM2 and GFAP, individually or sequentially, partially mediated the associations between NPTX and T-tau pathology, with stronger effects observed in the suspected non-AD pathology and Stage 2 groups. Pathway analysis suggested that NPTX may influence tau pathology and cognitive function through the sequential sTREM2→GFAP→T-tau or P-tau pathway.
    CONCLUSIONS: NPTX proteins are associated with tau-related pathology in AD, and CSF GFAP and sTREM2 may mediate these associations, with their roles potentially differing across stages of disease progression.
    Keywords:  Alzheimer’s disease; Astrocyte; Cerebrospinal fluid; Microglia; T-tau
    DOI:  https://doi.org/10.1186/s12974-025-03545-w
  5. Mol Neurodegener. 2025 Sep 29. 20(1): 101
    Making tracks: microglia and the extracellular matrix.
    Lauren K Wareham, David J Calkins.
      Microglia are resident immune cells of the central nervous system (CNS) and critical regulators of neural homeostasis, mediating immune surveillance, synaptic remodeling, debris clearance, and inflammatory signaling. Emerging evidence highlights the extracellular matrix (ECM) as important to microglial behavior in both physiological and pathological contexts. The CNS ECM is a dynamic and bioactive scaffold composed of three primary compartments: interstitial matrix, basement membranes at neurovascular and neuroepithelial interfaces, and perineuronal nets (PNNs). Each compartment exhibits distinct molecular architectures, ranging from fibrillar collagens and glycoproteins in basement membranes to chondroitin sulfate proteoglycans and hyaluronan-rich structures in PNNs. In this review we examine how microglia engage with and reshape the ECM to dynamically respond to disruptions in homeostasis with aging and disease. We discuss the concept of the microglial-ECM "interactome", which may represent a molecular interface through which microglia sense, modify, and respond to their extracellular environment. This interactome enables microglia to enact fine-scale ECM remodeling during routine surveillance, as well as large-scale alterations under pathological conditions to help preserve function and motility. In aging and disease, dysregulation of the microglial-ECM interactome is characterized by aberrant mechanotransduction, elevated proteinase activity, remodeling of the ECM, and sustained pro-inflammatory cytokine release. These pathological changes compromise ECM integrity, challenge microglial activity, and contribute to progressive neurovascular and synaptic dysfunction. Deciphering the molecular mechanisms underpinning microglial-ECM interactions is essential for understanding region-specific vulnerability in neurodegeneration and may reveal new therapeutic targets for preserving ECM structure and countering CNS disorders.
    Keywords:  Biomechanics; Blood-brain barrier; Cell motility; Extracellular matrix; Mechanotransduction; Microglia; Neurodegeneration
    DOI:  https://doi.org/10.1186/s13024-025-00898-x
  6. Science. 2025 Oct 02. 390(6768): eadr7403
    Intercellular communication in the brain through a dendritic nanotubular network.
    Minhyeok Chang, Sarah Krüssel, Laxmi Kumar Parajuli, Juhyun Kim, Daniel Lee, Alec Merodio, Jaeyoung Kwon, Shigeo Okabe, Hyung-Bae Kwon.
      Intercellular nanotubular networks mediate material exchange, but their existence in neurons remains to be explored in detail. We identified long, thin dendritic filopodia forming direct dendrite-dendrite nanotubes (DNTs) in mammalian cortex. Super-resolution microscopy in dissociated neurons revealed DNTs' actin-rich composition and dynamics, enabling long-range calcium ion (Ca2+) propagation. Imaging and machine learning-based analysis validated in situ DNTs as anatomically distinct from synaptic spines. DNTs actively transported small molecules and human amyloid-β (Aβ); DNT density increased before plaque formation in the medial prefrontal cortex of APP/PS1 mice (APP, Aβ precursor protein; PS1, presenilin-1), suggesting that the dendrite-DNT network might play a role in Alzheimer's disease pathology. Computational models of DNT-mediated Aβ propagation recapitulated early amyloidosis, predicting selective intracellular accumulation. These findings uncover a nanotubular connectivity layer in the brain, extending neuronal communication beyond classical synapses.
    DOI:  https://doi.org/10.1126/science.adr7403
  7. J Neuroinflammation. 2025 Oct 03. 22(1): 224
    Cytokine expression profile in the human brain of older adults.
    Juliana Beker Godoy, Ricardo A Vialle, Loren Dos Santos, Roberto T Raittz, Yanling Wang, Vilas Menon, Philip L De Jager, Julie A Schneider, Shinya Tasaki, David A Bennett, Dieval Guizelini, Katia de Paiva Lopes.
      Alzheimer's disease (AD) is a complex neurodegenerative condition linked to chronic neuroinflammation. This study investigates the cytokine gene expression profile in cortical tissue samples from elderly individuals with and without AD to identify potential biomarkers and enhance our understanding of disease pathogenesis. Utilizing high-depth RNA sequencing data, we identified a set of cytokines whose expression significantly associated with different aspects of the AD phenotype, including measures of neurofibrillary tangles, amyloid-β deposition, and a person-specific rate of cognitive decline. Single-nucleus transcriptomics data facilitated the identification of specific cell types, such as microglia and astrocytes, that significantly contribute to the inflammatory response in AD. Additionally, we observed a correlation between the expression of certain cytokines and genetic risk for the disease. Our findings indicate that cytokine-mediated neuroinflammation may play an important role in neurodegeneration and that modulating the immune response may offer a promising strategy for developing new therapies.
    Keywords:  Alzheimer’s disease; Biomarkers; Cytokines; Neuroinflammation; Single-nuclei RNA-Seq; Transcriptomics
    DOI:  https://doi.org/10.1186/s12974-025-03552-x
  8. Alzheimers Dement. 2025 Oct;21(10): e70746
    Amyloid beta and tau are associated with the dual effect of neuroinflammation on neurodegeneration.
    Guilherme Povala, Bruna Bellaver, Marco Antônio De Bastiani, João Pedro Ferrari-Souza, Cristiano S Aguzzoli, Douglas T Leffa, Pamela C L Ferreira, Firoza Z Lussier, Andreia Rocha, Hussein Zalzale, Carolina Soares, Guilherme Bauer-Negrini, Joseph Therriault, Nesrine Rahmouni, Jenna Stevenson, Stijn Servaes, Cécile Tissot, Bruno Zatt, Thomas K Karikari, Milos D Ikonomovic, Victor L Villemagne, Serge Gauthier, Eduardo R Zimmer, Dana L Tudorascu, Andrea L Benedet, Pedro Rosa-Neto, Tharick A Pascoal.
       INTRODUCTION: Current literature presents conflicting results regarding the impact of neuroinflammation on Alzheimer's disease (AD)-related neurodegeneration. While some studies suggest that neuroinflammation potentiates neurodegeneration, others indicate a protective effect.
    METHODS: We evaluated 145 individuals with positron emission tomography (PET) for amyloid beta (Aβ), tau, and translocator protein (TSPO), a proxy of neuroinflammation, to test the hypothesis that Aβ and tau are associated with the dual effect of neuroinflammation on neurodegeneration across the AD continuum.
    RESULTS: The detrimental effects of neuroinflammation on gray matter density occurred in two waves. The first neuroinflammation-related detrimental wave was associated with brain Aβ deposition, while the second was with widespread tau tangle pathology. Furthermore, the concomitant presence of neuroinflammation, Aβ, and tau was associated with faster cognitive decline over 2 years.
    CONCLUSIONS: Our results support a model in which Aβ- and tau-associated neuroinflammation are related to two waves of deleterious effects on AD-related neurodegeneration.
    HIGHLIGHTS: Two waves of detrimental neuroinflammation effects on brain density associated with Aβ or tau. Aβ associated with deleterious effect of neuroinflammation on brain density in early AD. Tau associated with deleterious effect of neuroinflammation on brain density in late AD. Interactions of Aβ, tau, and neuroinflammation are associated with cognitive decline.
    Keywords:  Alzheimer's disease; biomarkers; neurodegeneration; neuroinflammation; positron emission tomography
    DOI:  https://doi.org/10.1002/alz.70746
  9. J Neuroinflammation. 2025 Sep 29. 22(1): 218
    Modular inflammation network discovery from large-scale phenotypic screening in genetically heterogeneous mouse brains.
    Monica Xiong, Lisa A Miosge, Carolina Correa-Ospina, Claudia M Y Yan, Tiffany Cripps, Stefan Bauernfried, Yuanyuan Wang, Maggie Crow, Lucy X Morris, T Daniel Andrews, Andrew Trujillo, Mitchell G Rezzonico, Yuxin Liang, Qixin Bei, Zora Modrusan, Kimberly L Stark, Tracy J Yuen, Brad A Friedman, Jesse E Hanson, Edward M Bertram, Christopher J Bohlen.
      The central nervous system (CNS) represents a uniquely immune-privileged environment, with inflammatory responses involving several resident CNS-specific cell types. While stereotyped cellular and transcriptional responses recur across varied diseases, relevant signaling pathways and regulatory networks are not fully understood. Here, we investigate multi-modal inflammatory gene networks at large scale by developing a high-throughput RNA-seq screening and analysis workflow. As proof-of-concept, we investigate genetically heterogeneous mice from a large-scale chemical mutagenesis screen to identify novel functionally relevant variants in six genes previously linked to human CNS disorders: Nrros, Ctsd, Smpd1, Idua, Nlrp1a, and Inpp5d. We leverage the readily interpretable data from our large-scale study to demarcate distinct inflammatory states arising from each mutation. In all, our work provides a validated analysis framework for identifying discrete gene expression modules that are engaged divergently across disease contexts, which can be used to discover novel regulators of CNS neuroimmune homeostasis.
    Keywords:  Ctsd; ENU-mutagenesis; Inpp5d; Microglia; Nlrp1a; RNA-seq
    DOI:  https://doi.org/10.1186/s12974-025-03556-7
  10. Acta Neuropathol Commun. 2025 Sep 29. 13(1): 205
    Blocking axon-glial mechanotransduction to prevent concussive brain injury.
    Chao Sun, Di Ma, Jacob Hansen, Jeffrey R Tonniges, Hongzhen Hu, Liwen Zhang, Chen Gu.
      All cells in the central nervous system (CNS) are considered mechanosensitive, but how they collectively respond to a concussive head impact and contribute to the transition from the primary to secondary injury remains unknown. Using a mouse model for mild traumatic brain injury (mTBI) or concussion, we report that blocking the activity of TRPV4 transient receptor potential channels inhibits mTBI-induced sequential changes of neurons and glial cells, as well as behavioral disturbances. A concussive head impact immediately induces axonal varicosities, preceding NMDA-receptor-mediated microglial activation and cortical demyelination. Afterward, these changes differentially and partially recover. Blocking TRPV4 channels before or after head impact markedly suppresses axon-glial and behavioral changes or enhances their recovery, respectively. Using knockout mice and AAV-Cre-mediated acute and cell-type-specific deletion, we further show that neuronal TRPV4 channels, as an mTBI target, regulate the homeostasis of axon mechanosensation and their hyperactivation causes axonal varicosity formation followed by axon-to-glia mechanotransduction.
    DOI:  https://doi.org/10.1186/s40478-025-02117-6
  11. Alzheimers Dement. 2025 Oct;21(10): e70603
    Decoding adipose-brain crosstalk: Distinct lipid cargo in human adipose-derived extracellular vesicles modulates amyloid aggregation in Alzheimer's disease.
    Li Yang, Michael Chan, Jianting Sheng, Shaohua Qi, Bill Chan, Dharti Shantaram, Xilal Y Rima, Eduardo Reategui, Xianlin Han, Willa A Hsueh, Stephen T C Wong.
       INTRODUCTION: Obesity is a major modifiable risk factor for Alzheimer's disease (AD), but the mechanistic link between peripheral metabolic dysfunction and AD progression remains unclear. Adipose-derived extracellular vesicles (EVs) may penetrate the brain and alter lipid homeostasis, contributing to neurodegeneration.
    METHODS: We isolated exosome-enriched EVs from subcutaneous and visceral fat of lean and obese individuals, followed by lipidomic profiling. An in vitro amyloid-β (Aβ) aggregation assay using purified Aβ40 and Aβ42 peptides was performed under lipid environments mimicking physiological and pathological states.
    RESULTS: Obese-derived EVs exhibited distinct lipid profiles, particularly in lysophosphatidylcholine (LPC) and sphingomyelin (SM) species. Functional assays demonstrated that lipid identity and concentration critically influenced Aβ aggregation kinetics.
    DISCUSSION: Our study reveals that obesity-associated EV lipids modulate Aβ aggregation, linking adipose metabolism to AD pathology. These findings support lipid-targeted strategies as potential therapeutics for neurodegenerative diseases.
    HIGHLIGHTS: Human adipose-derived extracellular vesicles (EVs) from obese individuals exhibit distinct lipidomic profiles. EV lipids modulate amyloid-β (Aβ) 40 and Aβ42 aggregation in a lipid-type- and concentration-dependent manner. Lysophosphatidylcholine (LPC) and sphingomyelin (SM) species from obese EVs significantly deregulate Aβ fibrillization in vitro. EV lipid cargo links peripheral metabolic state to amyloid pathology in Alzheimer's disease.
    Keywords:  Alzheimer's disease; Aβ fibrillization; adipocyte‐derived extracellular vesicles; exosome‐enriched extracellular vesicles; lipid homeostasis; lipidomics; obesity
    DOI:  https://doi.org/10.1002/alz.70603
  12. Nat Commun. 2025 Sep 30. 16(1): 8724
    Munc13-1 restoration mitigates presynaptic pathology in spinal muscular atrophy.
    Mehri Moradi, Julia Weingart, Chunchu Deng, Mahoor Nasouti, Michael Briese, Sibylle Jablonka, Markus Sauer, Michael Sendtner.
      Degeneration of neuromuscular synapses is a key pathological feature of spinal muscular atrophy (SMA), yet cellular mechanisms underlying synapse dysfunction remain elusive. Here, we show that pharmacological stimulation with Roscovitine triggers the assembly of Munc13-1 release sites that relies on its local translation. Our findings show that presynaptic mRNA levels and local synthesis of Munc13-1 are diminished in motoneurons from SMA mice and hiPSC-derived motoneurons from SMA patients. Replacement of the Munc13-1 3'UTR with that of Synaptophysin1 rescues Munc13-1 mRNA transport in SMA motoneurons and restores the nanoscale architecture of presynaptic Munc13-1 release sites. Restoration of Munc13-1 levels leads to functional synaptic recovery in cultured SMA motoneurons. Furthermore, SMA mice cross-bred with a conditional knock-in mouse expressing modified Munc13-1 with a heterologous 3'UTR display attenuated synapse and neurodegeneration and improved motor function. Identifying Munc13-1 as an SMA modifier underscores the potential of targeting synapses to mitigate neuromuscular dysfunction in SMA.
    DOI:  https://doi.org/10.1038/s41467-025-64164-w
  13. Cell. 2025 Oct 02. pii: S0092-8674(25)01030-X. [Epub ahead of print]188(20): 5433-5435
    Decoding Alzheimer's disease at the cellular level reveals promising combination therapy.
    Kyle Coleman, Nicholas P Tatonetti.
      Alzheimer's disease (AD) has long resisted effective treatments due to its pathological heterogeneity and cell-type-specific regulatory changes. In this issue of Cell, Li et al. leverage single-cell RNA sequencing and drug repurposing to propose a promising combination therapy, validated through real-world evidence and mouse models, that targets multiple AD-relevant cell types.
    DOI:  https://doi.org/10.1016/j.cell.2025.08.037
  14. bioRxiv. 2025 Sep 25. pii: 2025.09.25.678630. [Epub ahead of print]
    Integrative analysis reveals generalizable human neurodegenerative disease-associated glial states.
    Liam Horan-Portelance, Dominic J Acri, Alexandra Mann, Janet Brooks, Hannah M Bailey, J Raphael Gibbs, Alex R DeCasien, Mark R Cookson.
      Disease-associated glia represent plastic transcriptional cellular states observed across neurodegenerative diseases (NDDs). In particular, microglial states have been characterized in Alzheimer's disease and mouse models of amyloidosis. Although single-cell transcriptomic technologies have increased the dimensionality of information available across cell states, few studies have systematically tested for changes in glial transcription across brain regions and disease states. Here, we report a statistical framework for glial annotation, disease association, and transcriptional profiling, which facilitate identification of generalizable glial states that are present across a spectrum of NDDs (Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Frontotemporal dementia). We identify seven astrocyte substates, 14 microglia/myeloid substates, and five oligodendrocyte substates where transcriptional variability is attributable to region, disease, or batch effects. Regional heterogeneity of astrocytes masked disease associations, even within cortical astrocytes. We found only limited oligodendrocyte transcriptional heterogeneity, resulting in few substates for further interrogation. Notably, microglia showed the strongest evidence for disease association. We show, for the first time, that this association exists across the entire NDD spectrum. Using latent factor analysis, we created a consensus human neurodegenerative disease-associated microglia (hnDAM) signature, which we experimentally validated in 11 independent sample series. We demonstrate that the hnDAM signature is a statistically testable biomarker for conserved microglial activation in NDDs by: i) comparing to murine DAM-like signatures, ii) performing transcription factor analysis, and iii) modeling transcriptional reprogramming perturbations in iPSC-derived microglia. Taken together, this work broadens our understanding of glial activation across neuropathologies and reveals hnDAM as a putative therapeutic target that can be widely generalized to patients suffering from NDDs.
    DOI:  https://doi.org/10.1101/2025.09.25.678630
This page is being maintained by Thomas Krichel. It was last updated on 2025‒11‒02 at 1:56.