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Published on: April 5, 2022
Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer's disease
Hongtian Stanley Yang1, Kristen D Onos1, Kwangbom Choi1
1The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Abstract:
Genetic and genome-wide association studies suggest a central role for microglia in Alzheimer's disease (AD). However, single-cell RNA sequencing (scRNA-seq) of microglia in mice, a key preclinical model, has shown mixed results regarding translatability to human studies. To address this, scRNA-seq of microglia from C57BL/6J (B6) and wild-derived strains (WSB/EiJ, CAST/EiJ, and PWK/PhJ) with and without APP/PS1 demonstrates that genetic diversity significantly alters features and dynamics of microglia in baseline neuroimmune functions and in response to amyloidosis. Results show significant variation in the abundance of microglial subtypes or states, including numbers of previously identified disease-associated and interferon-responding microglia, across the strains. For each subtype, significant differences in the expression of many genes are observed in wild-derived strains relative to B6, including 19 genes previously associated with human AD including Apoe, Trem2, and Sorl1. This resource is critical in the development of appropriately targeted therapeutics for AD and other neurological diseases.
Insights
Genetic diversity significantly impacts microglia function and states in Alzheimer's disease models. Understanding these variations is crucial for developing effective Alzheimer's disease therapeutics.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia play a key role in Alzheimer's disease (AD), as indicated by genetic studies.
- Single-cell RNA sequencing (scRNA-seq) of mouse microglia has yielded inconsistent results for human translatability.
- Preclinical models require careful consideration of genetic background for accurate AD research.
Purpose of the Study:
- To investigate the impact of genetic diversity on microglial characteristics and responses in Alzheimer's disease models.
- To assess how different mouse genetic backgrounds influence microglial states and gene expression, particularly in the context of amyloidosis.
- To identify genetic variations in microglia relevant to human Alzheimer's disease.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) was performed on microglia from C57BL/6J (B6) and three wild-derived mouse strains (WSB/EiJ, CAST/EiJ, PWK/PhJ).
- Mice were studied under both baseline conditions and in the presence of amyloid precursor protein/presenilin 1 (APP/PS1) transgene expression.
- Comparative analysis of microglial subtype abundance and gene expression profiles across different genetic backgrounds was conducted.
Main Results:
- Significant variations in microglial subtype abundance, including disease-associated and interferon-responding microglia, were observed across the different mouse strains.
- Wild-derived strains exhibited distinct gene expression patterns compared to the standard B6 strain.
- Differences in the expression of 19 genes, including key AD-associated genes like Apoe, Trem2, and Sorl1, were noted in wild-derived strains relative to B6.
Conclusions:
- Genetic diversity profoundly influences microglial neuroimmune functions and responses to amyloid pathology.
- The findings highlight the importance of considering genetic background in mouse models for Alzheimer's disease research.
- This study provides a valuable resource for developing targeted microglial-based therapeutics for AD and other neurological disorders.
