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Published on: December 26, 2016
Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer's disease model
Antara Rao1, Nuo Chen2, Min Joo Kim3
1Gladstone 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.
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.
Insights
Microglia and apolipoprotein E4 (APOE4) significantly influence Alzheimer's disease (AD) pathology. This study shows that microglia exacerbate AD when neurons express APOE4, highlighting their combined role in disease progression.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Apolipoprotein E4 (APOE4) and microglia are key players in Alzheimer's disease (AD).
- The specific impact of microglia on APOE4-driven AD pathogenesis is not fully understood.
- Understanding these interactions is crucial for developing targeted AD therapies.
Purpose of the Study:
- To investigate the role of microglia in neuronal APOE4-associated AD pathogenesis.
- To determine how microglial depletion affects amyloid-beta (Aβ) and tau pathologies in the presence of different APOE isoforms.
Main Methods:
- Chimeric mouse models were created by transplanting human induced pluripotent stem cell (iPSC)-derived neurons (expressing APOE4, APOE3, or no APOE) into mouse hippocampi.
- Microglia were depleted in a subset of these chimeric mice.
- Single-cell RNA sequencing was employed to analyze microglial subtypes and gene expression.
Main Results:
- Both neuronal apolipoprotein E (APOE) and the presence of microglia were essential for Aβ and tau pathology development.
- APOE4 significantly exacerbated pathology compared to APOE3.
- Two pro-inflammatory microglial subtypes with increased MHC-II expression were identified in mice with APOE4 neuron transplants.
Conclusions:
- Neuronal APOE, particularly APOE4, and microglia act in concert to drive AD pathogenesis.
- Microglia play a critical role in amplifying APOE4-related AD pathology.
- These findings underscore the therapeutic potential of targeting microglial activation in APOE4 carriers with AD.
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