Language

English

Publication Date

1-1-2026

Journal

Nature Neuroscience

DOI

10.1038/s41593-025-02115-w

PMID

41272323

PMCID

PMC13159067

PubMedCentral® Posted Date

5-12-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Astrocytes play essential roles in the brain, and their dysfunction is associated with nearly every form of neurological disease. Despite their ubiquity, knowledge of how astrocytes contribute to disease pathogenesis is incomplete; accordingly, harnessing their biology toward therapeutics remains a major challenge. Here we show that the transcription factor Sox9 plays a context-specific role in maintaining astrocyte function and circuit activity in the aging hippocampus and Alzheimer's disease (AD) models. We found that Sox9 overexpression in astrocytes in AD models clears existing amyloid beta (Aβ) plaques and preserves cognitive function. Mechanistically, Sox9 promotes the phagocytosis of Aβ plaques by astrocytes through the regulation of the phagocytic receptor MEGF10, which is sufficient to preserve cognitive function in AD models. Collectively, these studies highlight a role for astrocytic Sox9 during aging and AD while identifying Sox9-MEGF10 signaling as a prospective astrocyte-based therapeutic approach to ameliorate cognitive decline in neurodegenerative disease.

Keywords

Animals, SOX9 Transcription Factor, Alzheimer Disease, Astrocytes, Phagocytosis, Plaque, Amyloid, Mice, Mice, Transgenic, Disease Models, Animal, Cognition, Amyloid beta-Peptides, Male, Mice, Inbred C57BL, Hippocampus, Humans, Membrane Proteins

Comments

This article has been corrected. See Nat Neurosci. 2026 Apr 24.

Published Open-Access

yes

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