Enhancing TREM2 expression activates microglia and modestly mitigates tau pathology and neurodegeneration

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Triggering receptor expressed myeloid 2 (TREM2) is a microglia-specific receptor linked to Alzheimer's disease (AD) risk.
• TREM2 influences microglial responses to amyloid pathology, but its role in tau pathology and neurodegeneration is not fully understood.

Purpose of the Study:

• To investigate the impact of TREM2 variants on tau pathology and neurodegeneration in a mouse model.
• To elucidate the mechanisms by which TREM2 modulates microglial activation in the context of tauopathy.

Main Methods:

• Utilized the PS19 tauopathy mouse model with inducible overexpression of wild-type TREM2 (TREM2-WT) or the R47H variant (TREM2-R47H).
• Employed single-cell RNA sequencing to analyze microglial activation states.
• Assessed soluble phosphorylated tau levels and neuronal integrity.

Main Results:

• TREM2-WT overexpression reduced soluble phosphorylated tau and preserved neuronal integrity.
• TREM2-WT enhanced microglial activation, inducing a disease-associated microglia (DAM) signature.
• TREM2-R47H overexpression demonstrated a loss-of-function, with no significant effects on tau, neurodegeneration, or microglial activation.

Conclusions:

• TREM2 plays a crucial role in modulating microglial activity and influencing tau pathology and neurodegeneration.
• TREM2-WT enhances beneficial microglial responses, while the R47H variant may impair these functions.
• Findings offer insights into TREM2-targeted therapies for Alzheimer's disease and other tauopathies.