Functional BRI2-TREM2 interactions in microglia: implications for Alzheimer's and related dementias

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Mutations in ITM2B/BRI2 are linked to Alzheimer's Disease (AD)-related dementias.
• Microglia play a key role in AD pathogenesis, with TREM2 variants increasing risk.
• Heightened ITM2B/BRI2 expression is observed in microglia.

Purpose of the Study:

• To investigate the functional interaction between BRI2 and TREM2 in the context of AD.
• To determine if BRI2 influences TREM2 processing, similar to its effect on Aβ-Precursor-Protein.
• To explore BRI2 as a potential therapeutic target for AD and related dementias.

Main Methods:

• Single-cell RNA-sequencing to identify Trem2/Bri2-dependent microglia clusters.
• Investigating BRI2-TREM2 interaction in heterologous cells and using recombinant proteins.
• Utilizing constitutive and microglial-specific Itm2b-knock-out mouse models and primary microglia.
• Analyzing Trem2 processing, mRNA expression, and protein levels.
• Assessing phagocytosis in the context of Bri2 deletion and pathogenic TREM2 variants.

Main Results:

• A functional interaction between BRI2 and TREM2 was identified, inhibiting TREM2 processing.
• BRI2 directly interacts with the TREM2 ectodomain in a cell-free system.
• Bri2 deficiency in mice leads to reduced TREM2 processing, altered TREM2 mRNA and protein levels, and impaired microglial phagocytosis.
• A mutant Itm2b mouse model showed elevated Trem2-CTF and sTrem2, consistent with AD patient findings.
• Bri2 deletion phenocopies the phagocytic deficits observed with a pathogenic TREM2 variant.

Conclusions:

• BRI2 plays a multifaceted role in regulating TREM2 processing and function, independent of α-secretase pathways.
• The interaction between BRI2 and TREM2 impacts microglial function relevant to Alzheimer's Disease.
• BRI2 represents a promising therapeutic target for AD and related dementias due to its regulation of both Aβ-Precursor-Protein and TREM2.