Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer’s disease model

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Despite strong evidence supporting the important roles of both apolipoprotein E4 (APOE4) and microglia in Alzheimer’s disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-related AD pathogenesis remain elusive. To examine such effects, we utilized microglial depletion in a chimeric model with induced pluripotent stem cell (iPSC)-derived human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) iPSC-derived human neurons into the hippocampus of human APOE3 or APOE4 knockin mice and then depleted microglia in half of the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of Aβ and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA sequencing analysis identified two pro-inflammatory microglial subtypes with elevated MHC-II gene expression enriched in chimeric mice with human APOE4 neuron transplants. These findings highlight the concerted roles of neuronal APOE, especially APOE4, and microglia in AD pathogenesis. • In vivo chimeric modeling of human APOE4-related Alzheimer’s disease pathogenesis • Neuronal APOE4 promotes Aβ and p-tau pathologies in the chimeric mouse model • Microglial depletion reduces neuronal APOE4-induced Aβ and p-tau pathologies • Neuronal APOE4 promotes inflammatory response of microglia in the chimeric model Huang and colleagues examine the effects of APOE4 and microglial depletion on Alzheimer’s disease (AD) pathogenesis in a chimeric mouse model with transplanted human induced pluripotent stem cell-derived neurons. They demonstrate the importance of neuronal APOE and the role of both APOE4 and microglia in promoting AD pathologies.