Astrocyte priming enhances microglial Aβ clearance and is compromised by APOE4

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.

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Publication Details

Journal
Nature Communications
Published
2025-08-14
DOI
https://doi.org/10.1038/s41467-025-62995-1
Citations
14
Primary Topic
Immune responses and vaccinations
Type
article
Field-Weighted Citation Impact
11.16

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article

Astrocyte priming enhances microglial Aβ clearance and is compromised by APOE4

S.J. Lee, Jinsoo Seo, Sukhee Cho, Fan Gao et al.
14 citations
Nature Communications
Immune responses and vaccinations
11.16
article

Astrocyte priming enhances microglial Aβ clearance and is compromised by APOE4

S.J. Lee, Jinsoo Seo, Sukhee Cho, Fan Gao, Hong‐Hee Won, Min Jun Jang, Hyunji Jo, Younghoon Go, Buyun Kim, Malk Eun Pak, Min Soo Kim, Hyein Lee, Jae Kwang Kim, Na Yeon Kim, J. Jessica Yu
article en
14 citations

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.

Nature CommunicationsVol. 16(1)
Seoul National University of Science and Technology (KR), California Institute of Technology (US), Daegu Haany University (KR), Daegu Gyeongbuk Institute of Science and Technology (KR), Yonsei University (KR), Samsung Medical Center (KR), Kyung Hee University (KR), Korea Institute of Oriental Medicine (KR), Korea Institute of Brain Science (KR), Kyung Hee University Medical Center (KR), Korean Association Of Science and Technology Studies (KR), Korea Institute of Science and Technology (KR), Sungkyunkwan University (KR), Korea University of Science and Technology (KR), Daegu University (KR)
Korea Brain Research Institute, National Research Foundation, Korea Health Industry Development Institute, Korea Institute of Oriental Medicine, Ministry of Science and ICT, South Korea
Openalex Percentile: Top 1%
Immune responses and vaccinations
11.16
DOIOpen Access PDFOpenAlex
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