Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Missense mutations in the TREM2 gene increase Alzheimer's disease (AD) risk.
• TREM2 signaling is activated by Aβ and involves PLCG2, DAP12, and SYK.
• Understanding TREM2-PLCG2 interactions is key to dissecting AD cellular mechanisms.

Purpose of the Study:

• To investigate the TREM2-PLCG2 signaling cascade in microglia.
• To identify novel protein interactors and understand cellular mechanisms in AD.
• To elucidate the role of TREM2 signaling in microglia function.

Main Methods:

• Stimulation of TREM2 signaling in mouse microglia using Aβ and anti-TREM2 antibody.
• Western blotting to assess phosphorylation of signaling components.
• Co-immunoprecipitation and immunofluorescence to identify protein interactors.
• Cell migration and Aβ engulfment assays to measure functional readouts.

Main Results:

• The TREM2-DAP12-PLCG2 complex interacts with novel proteins in microglia.
• TREM2 activation significantly increased phospho-SYK and PLCG2 phosphorylation.
• Increased phospho-PLCG2 levels altered microglia functions, including migration and cargo engulfment.

Conclusions:

• TREM2 stimulation initiates a novel signaling cascade via PLCG2, mediating essential microglia functions.
• This pathway involves B cell receptor signaling components and AD-related genes.
• Elucidating the TREM2-PLCG2 pathway offers insights into microglia function and AD pathogenesis.