Lee, Se-In Yu, Jichang Lee, Hyein Kim, Buyun Jang, Min Jun Jo, Hyeonbin Kim, Na Yeon Pak, Malk Eun Kim, Jae Kwang Cho, Sukhee Won, Hong-Hee Kim, Min Soo Gao, Fan Go, Younghoon Seo, Jinsoo 2025-09-04T02:30:11Z 2025-09-04T02:30:11Z 2025-09-04 2025-08 https://pubs.kist.re.kr/handle/201004/153115 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. English Nature Publishing Group Astrocyte priming enhances microglial Aβ clearance and is compromised by APOE4 Article 10.1038/s41467-025-62995-1 1 Nature Communications, v.16, no.1 Nature Communications 16 1 Y scie scopus 001552511800040 2-s2.0-105013184147 Multidisciplinary Sciences Science & Technology - Other Topics Article PATHWAY GENE