Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer’s disease model
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.
Authors
- Maxine Nelson (ORCID: https://orcid.org/0000-0003-1990-5099)
- Zherui Liang (ORCID: https://orcid.org/0009-0001-7312-3410)
- Yadong Huang (ORCID: https://orcid.org/0000-0002-5871-4589)
- Seo Yeon Yoon (ORCID: https://orcid.org/0000-0002-0365-2923)
- Nicole Koutsodendris (ORCID: https://orcid.org/0000-0002-2761-1480)
- Brian P. Grone (ORCID: https://orcid.org/0000-0003-3737-2724)
- David Shostak (ORCID: https://orcid.org/0000-0002-1768-6374)
- Oscar Yip (ORCID: https://orcid.org/0000-0001-9096-7167)
- Yanxia Hao
- Jessica Blumenfeld (ORCID: https://orcid.org/0000-0002-5470-6901)
- Patrick Arriola
- Min Joo Kim (ORCID: https://orcid.org/0000-0002-7906-0115)
- Misha Zilberter (ORCID: https://orcid.org/0000-0001-7164-8312)
- Antara Rao (ORCID: https://orcid.org/0000-0002-1269-018X)
- Nuo Chen (ORCID: https://orcid.org/0009-0000-2895-746X)
- Leo Ding
Institutions
- Gladstone Institutes (US)
Publication Details
- Journal
- Cell stem cell
- Published
- 2024-11-04
- DOI
- https://doi.org/10.1016/j.stem.2024.10.005
- Citations
- 32
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 7.92
Funders
- National Science Foundation
- Gladstone Institutes
- James B. Pendleton Charitable Trust
- National Institutes of Health
- Defense Advanced Research Projects Agency
- National Institute on Aging