TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Microglia play a key role in Alzheimer's disease (AD) pathogenesis.
• Disease-associated microglia (DAM) are characterized by a specific transcriptional signature, often linked to the TREM2-DAP12-SYK pathway.
• The TREM2 R47H variant increases AD risk by impairing microglial activation via SYK.

Purpose of the Study:

• To investigate the role of SYK in microglial response to amyloid-beta (Aβ) plaques in AD.
• To elucidate the signaling pathways involved in microglial activation and DAM formation.
• To explore potential therapeutic strategies targeting SYK for AD treatment.

Main Methods:

• Utilized SYK-deficient microglia models to assess their response to Aβ.
• Analyzed the PI3K-AKT-GSK-3β-mTOR pathway in SYK-deficient microglia.
• Investigated the role of the DAP10 adapter protein in TREM2 signaling.
• Administered a CLEC7A antibody to TREM2 R47H variant mice to evaluate therapeutic efficacy.

Main Results:

• SYK-deficient microglia failed to encase Aβ plaques, leading to accelerated brain pathology and behavioral deficits.
• SYK deficiency disrupted the PI3K-AKT-GSK-3β-mTOR pathway, hindering the development of the DAM profile.
• Despite SYK deficiency, microglia proliferated and reached a prodromal DAM stage via the DAP10 pathway.
• Antibody-mediated activation of SYK through CLEC7A rescued microglial activation in TREM2 R47H mice.

Conclusions:

• Microglial Aβ response involves distinct, non-redundant SYK and DAP10 signaling pathways.
• SYK is essential for microglia to effectively manage Aβ pathology and prevent accelerated neurodegeneration.
• Targeting SYK activation, potentially via CLEC7A, presents a promising therapeutic avenue for Alzheimer's disease.