Lymphoid gene expression supports neuroprotective microglia function

• 成果类型: Article
• 署名作者: Ayata, Pinar; Crowley, Jessica M.; Challman, Matthew F.; Sahasrabuddhe, Vinaya; Gratuze, Maud; Werneburg, Sebastian; Ribeiro, Diogo; Hays, Emma C.; Duran-Laforet, Violeta; Faust, Travis E.; Hwang, Philip; Mendes Lopes, Francisco; Nikopoulou, Chrysa; Buchholz, Sarah; Murphy, Robert E.; Mei, Taoyu; Pimenova, Anna A.; Romero-Molina, Carmen; Garretti, Francesca; Patel, Tulsi A.; De Sanctis, Claudia; Ramirez Jimenez, Angie V.; Crow, Megan; Weiss, Felix D.; Ulrich, Jason D.; Marcora, Edoardo; Murray, John W.; Meissner, Felix; Beyer, Andreas; Hasson, Dan; Crary, John F.; Schafer, Dorothy P.; Holtzman, David M.; Goate, Alison M.; Tarakhovsky, Alexander; Schaefer, Anne
• 署名单位: Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; City University of New York (CUNY) System; Washington University (WUSTL); Aix-Marseille Universite; University of Massachusetts System; UMass Chan Medical School; University of Massachusetts Worcester; University of Michigan System; University of Michigan; Max Planck Society; University of Cologne; University of Cologne; University of Cologne; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Roche Holding; Roche Holding USA; Genentech; University of Bonn; Leibniz Association; Deutsches Rheuma-Forschungszentrum (DRFZ); Columbia University; Rockefeller University
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09662-z
• 发表日期: 2025-12-04
• 关键词: translational profiling approach; B-CELL DEVELOPMENT; PHOSPHOLIPASE C-GAMMA-2; transcription factors; LINEAGE COMMITMENT; alzheimers; beta; pu.1; platform; mouse

摘要

Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer's disease (AD)1. The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic2. Here we show that the protective function of microglia is governed by the transcription factor PU.1, which becomes downregulated following microglial contact with plaques. Lowering PU.1 expression in microglia reduces the severity of amyloid disease pathology in mice and is linked to the expression of immunoregulatory lymphoid receptor proteins, particularly CD28, a surface receptor that is critical for T cell activation3,4. Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated PU.1low microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load. Our findings indicate that PU.1low CD28-expressing microglia may operate as suppressive microglia that mitigate the progression of AD by reducing the severity of neuroinflammation. This role of CD28 and potentially other lymphoid co-stimulatory and co-inhibitory receptor proteins in governing microglial responses in AD points to possible immunotherapy approaches for treating the disease by promoting protective microglial functions.