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TYRO protein tyrosine kinase-binding protein (TYROBP), also known as DNAX-activation protein 12 (DAP12) and killer cell activating receptor-associated protein (KARAP), is the adaptor protein that mediates TREM2 signaling in microglial cells. Mutations in the TYROPB gene cause Nasu-Hakola disease, also known as PLOSL (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy), a recessively inherited disorder characterized by neurodegeneration and bone cysts. TYROBP has not been identified as a risk gene for Alzheimer’s disease in GWAS. However, in an exome sequencing study, rare coding variants in TYROPB were found to associate with risk for early onset Alzheimer’s disease—nine of 1,110 patients and none of 1,826 controls carried such a variant—although the p value did not reach exome-wide significance (Pottier et al., 2016). Moreover, network analysis of gene-expression data identified TYROBP as a regulatory hub in a module containing genes previously associated with AD risk in GWAS, which is reconfigured in AD (Zhang et al., 2013).

Expression of TYROBP is elevated in the brains of individuals with late-onset AD, compared with control subjects (Zhang et al., 2013). Tyrobp mRNA was selectively increased in plaque-associated microglia, compared with microglia distant from amyloid plaques, in mice carrying transgenes with AD-linked mutations (Audrain et al., 2021). In autopsy specimens from human AD patients and in the brains of mouse models of amyloidosis, DAP12 protein was seen to be concentrated in microglial processes contacting amyloid plaques (Yuan et al., 2016). Deletion of Tyropb reduced microglial coverage of amyloid plaques in the brains of APPPS1-21 mice and exacerbated plaque-associated neuritic dystrophy (Yuan et al., 2016).