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

Antara Rao; Nuo Chen; Min Joo Kim; Jessica Blumenfeld; Oscar Yip; Zherui Liang; David Shostak; Yanxia Hao; Maxine R Nelson; Nicole Koutsodendris; Brian Grone; Leo Ding; Seo Yeon Yoon; Patrick Arriola; Misha Zilberter; Yadong Huang

doi:10.1016/j.stem.2024.10.005

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

Cell Stem Cell. 2024 Oct 30:S1934-5909(24)00367-9. doi: 10.1016/j.stem.2024.10.005. Online ahead of print.

Authors

Affiliations

¹ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
² Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA, USA.
³ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
⁴ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
⁵ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
⁶ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA, USA; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA. Electronic address: [email protected].

PMID: 39500314
DOI: 10.1016/j.stem.2024.10.005

Abstract

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.

Keywords: APOE4; Alzheimer’s disease; RNA-seq; amyloid; chimeric disease model; iPSC; microglia; tau; transplantation.

Grants and funding

P01 AG073082/AG/NIA NIH HHS/United States