| First Author | Yin T | Year | 2024 |
| Journal | EMBO Rep | Volume | 25 |
| Issue | 3 | Pages | 1326-1360 |
| PubMed ID | 38347225 | Mgi Jnum | J:346614 |
| Mgi Id | MGI:7614189 | Doi | 10.1038/s44319-024-00077-x |
| Citation | Yin T, et al. (2024) Functional BRI2-TREM2 interactions in microglia: implications for Alzheimer's and related dementias. EMBO Rep 25(3):1326-1360 |
| abstractText | ITM2B/BRI2 mutations cause Alzheimer's Disease (AD)-related dementias. We observe heightened ITM2B/BRI2 expression in microglia, a pivotal cell type in AD due to risk-increasing variants in the microglial gene TREM2. Single-cell RNA-sequencing demonstrates a Trem2/Bri2-dependent microglia cluster, underscoring their functional interaction. alpha-secretase cleaves TREM2 into TREM2-CTF and sTREM2. As BRI2 hinders alpha-secretase cleavage of the AD-related Abeta-Precursor-Protein, we probed whether BRI2 influences TREM2 processing. Our findings indicate a BRI2-TREM2 interaction that inhibits TREM2 processing in heterologous cells. Recombinant BRI2 and TREM2 proteins demonstrate a direct, cell-free BRI2-TREM2 ectodomain interaction. Constitutive and microglial-specific Itm2b-Knock-out mice, and Itm2b-Knock-out primary microglia provide evidence that Bri2 reduces Trem2 processing, boosts Trem2 mRNA expression, and influences Trem2 protein levels through alpha-secretase-independent pathways, revealing a multifaceted BRI2-TREM2 functional interaction. Moreover, a mutant Itm2b dementia mouse model exhibits elevated Trem2-CTF and sTrem2, mirroring sTREM2 increases in AD patients. Lastly, Bri2 deletion reduces phagocytosis similarly to a pathogenic TREM2 variant that enhances processing. Given BRI2's role in regulating Abeta-Precursor-Protein and TREM2 functions, it holds promise as a therapeutic target for AD and related dementias. |
