Loss of TREM2 exacerbates parenchymal amyloid pathology but diminishes CAA in Tg-SwDI mice

Abstract

AbstractAlzheimer’s disease (AD) is a progressive neurodegenerative disease, and it is the most common cause of dementia worldwide. Recent genome-wide association studies (GWAS) identified TREM2 (triggering receptor expressed on myeloid cells 2) as one of the major risk factors for AD. TREM2 is a surface receptor expressed on microglia and largely mediates microglial functions and immune homeostasis in the brain. The functions of TREM2 in AD pathogenesis, including in the formation of the key pathology parenchymal amyloid-β (Aβ) plaques, have been investigated by introducingTrem2deficiency in AD mouse models. However, the role of TREM2 in cerebrovascular amyloidosis, in particular cerebral amyloid angiopathy (CAA) remains unexplored. CAA features Aβ deposition along the cerebral vessels, signifying an intersection between AD and vascular dysfunction. Using a well-characterized CAA-prone, transgenic mouse model of AD, Tg-SwDI (SwDI), we found that loss of TREM2 led to a marked increase in overall Aβ load in the brain, but a dramatic decrease in CAA in microvessel-rich regions, along with reduced microglial association with CAA. Transcriptomic analysis revealed that in the absence ofTrem2, microglia were activated but trapped in transition to the fully reactive state. Like microglia, perivascular macrophages were activated with upregulation of cell junction related pathways inTrem2-deficient SwDI mice. In addition, vascular mural cells and astrocytes exhibited distinct responses toTrem2deficiency, contributing to the pathological changes in the brain ofTrem2-null SwDI mice. Our study provides the first evidence that TREM2 differentially modulates parenchymal and vascular Aβ pathologies, which may have significant implications for both TREM2- and Aβ-targeting therapies for AD.