Abstract
Cerebral amyloid angiopathy (CAA), a major vascular contributor to cognitive decline, is present in 85–95% of Alzheimer’s disease (AD) patients. Despite its high prevalence, the mechanisms by which CAA contributes to neurodegeneration remain poorly understood. Triggering receptor expressed on myeloid cells 2 (TREM2), an innate immune receptor expressed exclusively by microglia, regulates activation, phagocytosis, and amyloid clearance, thereby shaping neuroinflammation. Loss-of-function mutations in TREM2 markedly increase AD risk, but its role in CAA pathology remains unknown. To investigate this, we crossed the Familial Danish Dementia (Tg-FDD) mouse model, which accumulates robust vascular amyloid, with TREM2 knockout (TREM2KO) mice to generate Tg-FDD/TREM2KO animals. Histological and transcriptomic analyses revealed region-specific effects of TREM2 deficiency. In the cortex, TREM2 loss markedly reduced vascular amyloid deposition, accompanied by decreased tau pathology. In contrast, in the cerebellum, TREM2 deletion exacerbated vascular amyloid accumulation, promoted astrogliosis, and enhanced tau pathology. Transcriptomic profiling further identified distinct neuroinflammatory signatures between cortex and cerebellum, particularly in cytokine signaling, matrix remodeling, and lipid metabolism. Together, these findings demonstrate that TREM2 deficiency leads to region-specific effects on CAA, revealing extensive regional variability in vascular amyloid pathology and underscoring the importance of considering these differences when developing TREM2-based therapies.