All Roads Lead to TREM2: Gearing Up to Target This Receptor

Cruchaga lab paired genomics and proteomics to research factors involved in TREM2 signaling and shedding. By compiling CSF samples from more than 3000 participants, they measured sTREM2 and ran a GWAS to find variants associated with protein levels.

Their findings:

1) Carriers of the p.R47H AD risk variant tended to have less sTREM2 in their CSF than non-carriers.

2) Two variants within this multigene locus (MS4a4a and MS4a6a) are both associated with higher sTREM2 levels.

3) A GWAS signal popped up in the ApoE locus, which has been associated with high mRNA expression of the Nectin-2 gene and its encoded protein PVRL2, hinting that PVRL2 might play a role in AD risk by influencing TREM2 homeostasis.

4) A hit came in from a locus containing RBMS3 and TGFBR2, further experiments suggesting that TGFBR2 is the one influencing the CSF sTREM2.

5)Among participants, higher CSF sTREM2 correlated with a reduced risk of AD.

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