{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T01:26:22Z","timestamp":1793496382519,"version":"4.5.0"},"posted":{"date-parts":[[2025,3,28]]},"group-title":"Neuroscience","reference-count":68,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T00:00:00Z","timestamp":1743120000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,28]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Human microglial heterogeneity is only beginning to be appreciated at the molecular level. Here, we present a large, single-cell atlas of expression signatures from 441,088 live microglia broadly sampled across a diverse set of brain regions and neurodegenerative and neuroinflammatory diseases obtained from 161 donors sampled at autopsy or during a neurosurgical procedure. Using single-cell hierarchical Poisson factorization (scHPF), we derived a 23-factor model for continuous gene expression signatures across microglia which capture specific biological processes (e.g., metabolism, phagocytosis, antigen presentation, inflammatory signaling, disease-associated states). Using external datasets, we evaluated the aspects of microglial phenotypes that are encapsulated in various\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  microglia models and identified and replicated the role of two factors in human postmortem tissue of Alzheimer\u2019s disease (AD). Further, we derived a complex network of transcriptional regulators for all factors, including regulators of an AD-related factor enriched for the mouse disease-associated microglia 2 (DAM2) signature:\n                  <jats:italic>ARID5B<\/jats:italic>\n                  ,\n                  <jats:italic>CEBPA<\/jats:italic>\n                  ,\n                  <jats:italic>MITF<\/jats:italic>\n                  , and\n                  <jats:italic>PPARG<\/jats:italic>\n                  . We replicated the role of these four regulators in the AD-related factor and then designed a multiplexed MERFISH panel to assess our microglial factors using spatial transcriptomics. We find that, unlike cells with high expression of the interferon-response factor, cells with high expression of the AD DAM2-like factor are widely distributed in neocortical tissue. We thus propose a novel analytic framework that provides a taxonomic approach for microglia that is more biologically interpretable and use it to uncover new therapeutic targets for AD.\n                <\/jats:p>","DOI":"10.1101\/2025.03.27.641500","type":"posted-content","created":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T01:39:50Z","timestamp":1743298790000},"source":"Crossref","is-referenced-by-count":17,"title":["A factor-based analysis of individual human microglia uncovers regulators of an Alzheimer-related transcriptional signature"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1762-4819","authenticated-orcid":false,"given":"Victoria S.","family":"Marshe","sequence":"first","affiliation":[{"name":"Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, 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