The gain-of-function TREM2-T96K mutation increases risk for Alzheimer's disease by impairing microglial function

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.