Astrocyte priming enhances microglial Aβ clearance and is compromised by APOE4

Authors
Lee, Se-InYu, JichangLee, HyeinKim, BuyunJang, Min JunJo, HyeonbinKim, Na YeonPak, Malk EunKim, Jae KwangCho, SukheeWon, Hong-HeeKim, Min SooGao, FanGo, YounghoonSeo, Jinsoo
Issue Date
2025-08
Publisher
Nature Publishing Group
Citation
Nature Communications, v.16, no.1
Abstract
The innate immune system can develop a form of memory called priming, where prior exposure to a stimulus enhances subsequent responses. While well-characterized in peripheral immunity, its function in brain-resident cells such as astrocytes under non-disease conditions remains unclear. Here we show that human astrocytes derived from the induced pluripotent stem cells of healthy female donors, but not microglia, acquire a primed state following transient immune stimulations. Upon subsequent exposure to amyloid-beta (A beta), these astrocytes secrete elevated levels of cytokines and promote microglial A beta uptake. In contrast, astrocytes carrying the Alzheimer's disease (AD) risk allele APOE4 exhibit reduced priming and fail to support microglial phagocytosis. These findings are validated in astrocyte-microglial co-cultures, cerebral organoids, and male mice, where astrocyte priming enhances A beta clearance in an APOE4-sensitive manner. Our findings identify astrocytic immune memory as a modulator of microglial function and A beta pathology, providing insights into how early protective responses in AD may be disrupted by genetic risk factors.
Keywords
PATHWAY; GENE
URI
https://pubs.kist.re.kr/handle/201004/153115
DOI
10.1038/s41467-025-62995-1
Appears in Collections:
KIST Article > Others
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