Fig. 3

Schematic illustration of sTREM2 production in microglia. This diagram illustrates two primary mechanisms underlying the generation of sTREM2: the proteolytic cleavage pathway and the splicing pathway. In the proteolytic cleavage pathway, the ectodomain of TREM2 is cleaved by metalloproteases, with ADAM10/17 cleaving at the H157-S158 bond and meprin β cleaving at the R136-D137 bond, resulting in the release of sTREM2 into the extracellular space. Alternatively, in the splicing pathway, mRNA variants of TREM2 are generated through splicing events, producing soluble forms of TREM2 that are also released extracellularly. Specifically, ENST00000373113 represents the canonical TREM2 transcript, consisting of five exons, while ENST00000338469 lacks exon 4, which encodes the transmembrane domain. Additionally, ENST00000373122 lacks exon 5 and has an alternative start site at exon 4, resulting in a different coding sequence. The box in the middle highlights the genetic modifiers influencing sTREM2 levels in the CSF