Astrocyte priming enhances microglial Aβ clearance and is compromised by APOE4

Se-In Lee, Jichang Yu, Hyein Lee, Buyun Kim, Min Jun Jang, Hyeonbin Jo, Na Yeon Kim, Malk Eun Pak, Jae Kwang Kim, Sukhee Cho, Hong-Hee Won, Min Soo Kim, Fan Gao, Younghoon Go () and Jinsoo Seo ()
Additional contact information
Se-In Lee: Daegu Gyeongbuk Institute of Science and Technology
Jichang Yu: Daegu Gyeongbuk Institute of Science and Technology
Hyein Lee: Daegu Gyeongbuk Institute of Science and Technology
Buyun Kim: Korea Institute of Oriental Medicine
Min Jun Jang: Korea Institute of Science and Technology (KIST)
Hyeonbin Jo: Samsung Medical Center
Na Yeon Kim: Daegu Gyeongbuk Institute of Science and Technology
Malk Eun Pak: Korea Institute of Oriental Medicine
Jae Kwang Kim: Daegu Hanny University
Sukhee Cho: Daegu Gyeongbuk Institute of Science and Technology
Hong-Hee Won: Samsung Medical Center
Min Soo Kim: Korea Institute of Science and Technology (KIST)
Fan Gao: Beckman Institute of Caltech
Younghoon Go: Korea Institute of Oriental Medicine
Jinsoo Seo: Daegu Gyeongbuk Institute of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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-β (Aβ), these astrocytes secrete elevated levels of cytokines and promote microglial Aβ 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 Aβ clearance in an APOE4-sensitive manner. Our findings identify astrocytic immune memory as a modulator of microglial function and Aβ pathology, providing insights into how early protective responses in AD may be disrupted by genetic risk factors.

Date: 2025
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DOI: 10.1038/s41467-025-62995-1

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