Lymphoid gene expression supports neuroprotective microglia function

Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer's disease (AD)<sup>1</sup>. The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic<sup>2</sup>. 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 activation<sup>3,4</sup>. Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated PU.1<sup>low</sup> microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load. Our findings indicate that PU.1<sup>low</sup> 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.

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Publication Details

Journal
Nature
Published
2025-11-05
DOI
https://doi.org/10.1038/s41586-025-09662-z
Citations
9
Primary Topic
Neuroinflammation and Neurodegeneration Mechanisms
Type
article
Field-Weighted Citation Impact
7.58
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article

Lymphoid gene expression supports neuroprotective microglia function

Carmen Romero‐Molina, Philip Hwang, Emma C. Hays, Richard Murphy et al.
9 citations
Nature
Neuroinflammation and Neurodegeneration Mechanisms
7.58
article

Lymphoid gene expression supports neuroprotective microglia function

Carmen Romero‐Molina, Philip Hwang, Emma C. Hays, Richard Murphy, Vinaya Sahasrabuddhe, Francesca Garretti, John W. Murray, Maud Gratuze, Andreas Beyer, Edoardo Marcora, Sarah Buchholz, Angie V. Ramirez Jimenez, Chrysa Nikopoulou, Sebastian Werneburg, Tulsi Patel, Violeta Durán‐Laforet, Jason D. Ulrich, Pinar Ayata, Anna A. Pimenova, Felix D. Weiss, John F. Crary, Diogo Ribeiro, Dorothy P. Schafer, Travis E. Faust, Felix Meissner, Megan Crow, Anne Schaefer, David M. Holtzman, Alison Goate, Alexander Tarakhovsky, Taoyu Mei, Dan Hasson, Claudia De Sanctis, Francisco Mendes Lopes, John Crowley, Matthew F. Challman
article en
9 citations

Abstract

Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer's disease (AD)<sup>1</sup>. The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic<sup>2</sup>. 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 activation<sup>3,4</sup>. Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated PU.1<sup>low</sup> microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load. Our findings indicate that PU.1<sup>low</sup> 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.

NatureVol. 648(8092)
The Graduate Center, CUNY (US), Centre National de la Recherche Scientifique (FR), Allen Institute for Brain Science (US), University of Bonn (DE), University of Massachusetts Chan Medical School (US), University of Cologne (DE), Leibniz Association (DE), Neuropsychiatric Research Institute (US), German Rheumatism Research Centre (DE), Institut de Neurophysiopathologie (FR), Hope Center for Neurological Disorders (US), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), University Hospital Cologne (DE), Max Planck Institute for Biology of Ageing (DE), Columbia University (US), Rockefeller University (US), Icahn School of Medicine at Mount Sinai (US)
Openalex Percentile: Top 2%
Neuroinflammation and Neurodegeneration Mechanisms
7.58
DOIOpen Access PDFOpenAlex
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