Discussion
Our study provides the first evidence that TREM2 differentially modulates parenchymal and vascular Aβ pathologies, offering significant implications for both TREM2- and Aβ-targeting therapies for AD. Highlights: Triggering receptor expressed on myeloid cells 2 (TREM2) differentially modulates brain parenchymal and vascular amyloidosis. Loss of Trem2 markedly reduces cerebral amyloid angiopathy despite an overall increase of amyloid beta load in Tg-SwDI mice. Microglia are trapped in transition to the fully reactive state without Trem2. Perivascular macrophages and other vascular cells have distinct responses to Trem2 deficiency. Balanced TREM2-targeting therapies may be required for optimal outcomes.
Methods
Tg-SwDI (SwDI) mice, a CAA-prone model of AD, and Trem2 knockout mice were crossed to generate SwDI/TWT, SwDI/THet, and SwDI/TKO mice, followed by pathological and biochemical analyses at 16 months of age.
Results
Loss of Trem2 led to a dramatic decrease in CAA and microglial association, despite a marked increase in overall brain Aβ load. Single nucleus RNA sequencing analysis revealed that in the absence of Trem2, microglia were activated but trapped in transition to the fully reactive state, with distinct responses of vascular cells.