Astrocyte priming enhances microglial Aβ clearance and is compromised by APOE4

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.