Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer's Disease Model

Rao, A.; Chen, N.; Kim, M. J.; Blumenfeld, J.; Yip, O.; Hao, Y.; Liang, Z.; Nelson, M. R.; Koutsodendris, N.; Grone, B.; Ding, L.; Yoon, S. Y.; Arriola, P.; Huang, Y.

doi:10.1101/2023.11.10.566510

bioRxiv · 10.1101/2023.11.10.566510

Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer's Disease Model

Rao, A.·Chen, N.·Kim, M. J.·Blumenfeld, J.·Yip, O.·Hao, Y.·Liang, Z.·Nelson, M. R.·Koutsodendris, N.·Grone, B.·Ding, L.·Yoon, S. Y.·Arriola, P.·Huang, Y.

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Abstract

Despite strong evidence supporting the involvement of both apolipoprotein E4 (APOE4) and microglia in Alzheimers Disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-driven AD pathogenesis remain elusive. Here, we examined such effects utilizing microglial depletion in a chimeric model with human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) induced pluripotent stem cell (iPSC)-derived human neurons into the hippocampus of human APOE3 or APOE4 knock-in mice, and depleted microglia in half the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of A{beta} and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA-sequencing analysis identified two pro-inflammatory microglial subtypes with high MHC-II gene expression that are 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. HIGHLIGHTSO_LITransplanted human APOE4 neurons generate A{beta} and p-tau aggregates in APOE4-KI mouse hippocampus. C_LIO_LIHuman neuronal APOE4 promotes the formation of dense-core A{beta} plaques and p-tau aggregates. C_LIO_LIMicroglia is required for human neuronal APOE4-driven formation of p-tau aggregates. C_LIO_LIscRNA-seq reveals enrichment of MHC-II microglia in mice with human APOE4 neuron transplants. C_LI

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Rao, A., Chen, N., Kim, M. J., Blumenfeld, J., Yip, O., Hao, Y., Liang, Z., Nelson, M. R., Koutsodendris, N., Grone, B., Ding, L., Yoon, S. Y., Arriola, P., Huang, Y.. 2023-11-14. Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer's Disease Model. https://doi.org/10.1101/2023.11.10.566510

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