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Published on: December 26, 2016
Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer's Disease Model
Antara Rao1,2, Nuo Chen1,3, Min Joo Kim1,4
1Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
Abstract:
Despite strong evidence supporting the involvement of both apolipoprotein E4 (APOE4) and microglia in Alzheimer's 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 Aβ 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.
Insights
Microglia and apolipoprotein E4 (APOE4) play key roles in Alzheimer's Disease (AD). This study shows that microglia exacerbate APOE4-driven AD pathology, highlighting their combined impact.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Apolipoprotein E4 (APOE4) is a major genetic risk factor for Alzheimer's Disease (AD).
- Microglia, the brain's immune cells, are implicated in AD pathogenesis.
- The interplay between neuronal APOE isoforms and microglia in AD is not fully understood.
Approach:
- A chimeric mouse model was developed using human induced pluripotent stem cell (iPSC)-derived neurons with different APOE genotypes (APOE4, APOE3, APOE-knockout).
- These human neurons were transplanted into the hippocampus of mice expressing human APOE3 or APOE4.
- Microglia were depleted in a subset of these chimeric mice to assess their specific contribution.
Key Points:
- Both neuronal apolipoprotein E (APOE) and the presence of microglia are crucial for the development of amyloid-beta (Aβ) and tau pathologies.
- The APOE4 isoform significantly enhanced pathology formation compared to APOE3.
- Single-cell RNA-sequencing revealed two pro-inflammatory microglial subtypes, characterized by high MHC-II expression, enriched in APOE4 neuron transplant models.
Conclusions:
- Neuronal APOE, particularly the APOE4 isoform, collaborates with microglia to drive Alzheimer's Disease pathogenesis.
- Targeting microglial activation in the context of APOE4 may offer a therapeutic strategy for AD.
