APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation

The ε4 allele of APOE-encoding apolipoprotein (ApoE) is one of the strongest genetic risk factors for Alzheimer’s disease (AD). One of the overarching questions is whether and how this astrocyte-enriched risk factor initiates AD-associated pathology in neurons such as amyloid-β (Aβ) accumulation. Here, we generate neurons and astrocytes from isogenic human induced pluripotent stem cells (hiPSCs) carrying either APOE ε3 or APOE ε4 allele and investigate the effect of astrocytic ApoE4 on neuronal Aβ production. Secretory factors in conditioned media from ApoE4 astrocytes significantly increased amyloid precursor protein (APP) levels and Aβ secretion in neurons. We further found that increased cholesterol secretion from ApoE4 astrocytes was necessary and sufficient to induce the formation of lipid rafts that potentially provide a physical platform for APP localization and facilitate its processing. Our study reveals the contribution of ApoE4 astrocytes to amyloidosis in neurons by expanding lipid rafts and facilitating Aβ production through an oversupply of cholesterol. [Display omitted] •ApoE4 ACM induces neuronal lipid raft expansion and Aβ42 overproduction•Co-localization of lipid rafts and APP increases in neurons by ApoE4 ACM•Increasing cholesterol in media recapitulates the effects of ApoE4 ACM on neurons•Cholesterol depletion in ApoE4 ACM abolishes its effects on neurons In this report, Seo and colleagues use human iPSCs to generate isogenic neurons and astrocytes carrying either APOE ε3 or APOE ε4 allele and demonstrate that ApoE4 astrocytes secrete more cholesterol to the extracellular space, which is sufficient and necessary to induce lipid raft expansion and Aβ42 overproduction in neurons.