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Published on: December 26, 2016
The gain-of-function TREM2-T96K mutation increases risk for Alzheimer's disease by impairing microglial function
Dominika J Pilat1, Hoang Le1, Dmitry Prokopenko1
1Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Abstract:
We previously reported that T96K is a gain-of-function mutation in TREM2 based on its ability to increase ligand-dependent activation. Here, we show that TREM2T96K increases risk for Alzheimer's disease (AD) in a whole-genome sequencing dataset comprised of family-based and case-control samples. Trem2T96K also reduced clustering of microglia around β-amyloid (Aβ) plaques exclusively in female 5xFAD mice. Furthermore, T96K decreased levels of soluble Trem2 in female 5xFAD mice and human microglial cell cultures. We also observed impaired uptake of Aβ in Trem2T96K knockin microglial cells. Moreover, Trem2T96K reduced total area of phagocytic microglia, specifically in female 5xFAD mice. Single-cell RNA sequencing (scRNA-seq) profiling of microglia revealed that Trem2T96K impairs the transition of homeostatic microglia into disease-associated microglia (DAM) in female 5xFAD mice. Downregulated inflammatory pathways associated with Trem2T96K included interleukin (IL)-6/JAK/STAT3, complement, and interferon (IFN)-γ response. Collectively, our results indicate that, like the loss-of-function mutation R47H, Trem2T96K adversely affects microglial function in a sex-dependent manner.
Insights
The TREM2 T96K mutation increases Alzheimer's disease risk and impairs microglial function, particularly in females. This gain-of-function mutation affects amyloid plaque interaction and the transition to disease-associated microglia.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- The TREM2 gene plays a crucial role in microglial function.
- Gain-of-function mutations in TREM2 can influence Alzheimer's disease (AD) risk.
- Previous work identified T96K as a gain-of-function TREM2 mutation.
Purpose of the Study:
- To investigate the impact of the TREM2 T96K mutation on Alzheimer's disease risk.
- To examine the functional consequences of TREM2 T96K on microglial behavior and inflammatory pathways.
- To determine if the effects of TREM2 T96K are sex-dependent.
Main Methods:
- Whole-genome sequencing of family-based and case-control samples.
- Analysis of microglia clustering around amyloid plaques in female 5xFAD mice.
- Measurement of soluble TREM2 levels in mouse models and human cell cultures.
- Assessment of amyloid-beta (Aβ) uptake and microglial phagocytic activity.
- Single-cell RNA sequencing (scRNA-seq) of microglia.
- Analysis of inflammatory pathway gene expression.
Main Results:
- TREM2 T96K mutation was associated with increased Alzheimer's disease risk.
- TREM2 T96K reduced microglial clustering around Aβ plaques and impaired Aβ uptake, exclusively in female mice.
- The mutation decreased soluble TREM2 levels in female mice and human microglial cultures.
- TREM2 T96K hindered the transition of homeostatic microglia to disease-associated microglia (DAM) in female mice.
- Downregulation of key inflammatory pathways (IL-6/JAK/STAT3, complement, IFN-γ) was observed.
Conclusions:
- The TREM2 T96K mutation confers risk for Alzheimer's disease.
- TREM2 T96K adversely affects microglial function, including Aβ clearance and DAM transition, in a sex-dependent manner.
- These findings highlight the complex role of TREM2 variants in AD pathogenesis and suggest potential sex-specific therapeutic targets.
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