Trem2 Knockin mouse models

Trem2 is the mouse ortholog of human TREM2 and encodes a single immunoglobulin domain innate receptor on microglia and other myeloid cells that lacks its own signaling motifs and instead pairs with Tyrobp, also called DAP12, to trigger Syk, PI3K and PLC gamma signaling after binding anionic lipids, apolipoprotein E and amyloid beta, licensing the disease-associated microglial state, phagocytosis and plaque compaction. ADAM10 and ADAM17 shed the ectodomain to produce soluble TREM2, an established cerebrospinal fluid biomarker whose signaling role is distinct from the membrane receptor. Allele choice here is unusually consequential because the R47H Alzheimer risk variant introduced into mouse Trem2 created a cryptic splice site that lowered transcript and confounded early reports, so humanized TREM2 knockins carrying the human sequence are required for variant modeling. Conditional nulls with microglia-restricted inducible Cre address adult requirement. Read plaque-associated microglial coverage, transcriptional signatures, and shed ectodomain levels.

Knockin designs at Trem2 support head to head comparisons between wild type and modified alleles because regulatory DNA stays in place.