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A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Trem2 R47H mutation shows mild, but functionally divergent alterations in microglial phenotypes compared to Trem2
Keiro Shirotani1, Daisuke Hatta1, Kaori Watanabe2
1Department of Genome-based Drug Discovery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan; Leading Medical Research Core Unit, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan.
Abstract:
The TREM2 R47H variant increases the risk of Alzheimer's disease (AD), yet its functional impact in aged mouse models remains incompletely understood. We generated a humanized Trem2 R47H knock-in (KI) line on the AppNL-F background and compared it with a Trem2 knockout (KO) line to assess the degree of TREM2 functional impairment. Accumulation of amyloid β 42 and formation of dystrophic neurites were increased in Trem2 KO mice but not in Trem2 R47H KI mice at 18 or 24 months. qPCR and transcriptomic analyses revealed Trem2 KO mice showed deficits in upregulation of microglial genes while Trem2 R47H KI mice showed a response similar to control mice. Differential gene expression analysis identified altered expressions of genes responsible for ER stress/unfolded protein response and intracellular signalling in Trem2 R47H KI mice. Among the differentially expressed genes, Pmel and Gpnmb were or tended to be downregulated in Trem2 R47H KI as well as in Trem2 KO mice indicating their involvement in AD pathogenesis. These results clearly indicate that the TREM2 R47H variant confers a mild, rather than null, effect on microglial alterations during AD development and that Trem2 R47H KI mice should be used to understand pathological mechanism elicited by TREM2. Further identification and characterization of genes differentially expressed in Trem2 R47H KI mice will provide important insights into how the TREM2 risk variant modulates Alzheimer's disease-related pathology.
Insights
The TREM2 R47H variant in Alzheimer's disease (AD) shows a mild effect on microglia, unlike complete loss-of-function. This TREM2 R47H knock-in mouse model is crucial for studying AD pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- The TREM2 R47H variant is a known risk factor for Alzheimer's disease (AD).
- The precise functional impact of TREM2 R47H in AD pathogenesis is not fully understood.
- Previous studies often used TREM2 knockout models, which represent a complete loss of function.
Purpose of the Study:
- To investigate the functional consequences of the TREM2 R47H variant in an AD mouse model.
- To compare the effects of TREM2 R47H knock-in with TREM2 knockout.
- To characterize microglial responses and gene expression changes associated with TREM2 R47H.
Main Methods:
- Generation of a humanized Trem2 R47H knock-in (KI) mouse line on the AppNL-F background.
- Comparison of Trem2 R47H KI mice with Trem2 knockout (KO) mice.
- Analysis of amyloid-beta (Aβ42) accumulation, neuritic dystrophy, qPCR, and transcriptomics.
Main Results:
- Trem2 KO mice showed increased Aβ42 and dystrophic neurites, unlike Trem2 R47H KI mice.
- Trem2 KO mice exhibited deficits in microglial gene upregulation, while Trem2 R47H KI mice showed responses similar to controls.
- Differential gene expression in Trem2 R47H KI mice revealed alterations in ER stress, unfolded protein response, and intracellular signaling pathways; Pmel and Gpnmb were downregulated.
Conclusions:
- The TREM2 R47H variant exerts a mild, not null, effect on microglial function during AD development.
- The Trem2 R47H KI mouse model is suitable for studying the specific pathological mechanisms of this TREM2 risk variant.
- Further research on differentially expressed genes in Trem2 R47H KI mice will elucidate TREM2's role in AD pathology.
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