TREM2 differentially modulates parenchymal and vascular pathology in a mouse model of cerebral amyloid angiopathy

Background: Cerebral amyloid angiopathy (CAA) features cerebral vascular deposition of pathological amyloid-beta protein (Aβ) and plays an important role in the multimorbidity of aging brains including Alzheimer’s disease (AD), but it is less understood compared to parenchymal Aβ plaques. Triggering receptor expressed on myeloid cells 2 (TREM2), a key player in innate immune response, is exclusively expressed in microglia in the brain and mediates Aβ clearance and subsequently alleviates neuroinflammation. Loss-of-function mutations in TREM2 increase the risk of AD. Recent studies on TREM2 function using TREM2 knockout (KO) in transgenic (Tg) AD mice have shown that TREM2 modulates parenchymal Aβ deposition in the brain, although the direction of the effect depends on the specific Tg background and the stage of the disease development. However, the impact of TREM2 on CAA had not been investigated. Methods: TREM2 KO mice were crossed with SwDI mice (C57BL/6-Tg(Thy1-APPSwDutIowa)BWevn/Mmjax), a model of CAA and AD, to generate SwDI/TREM2WT, SwDI/TREM2Het, and SwDI/TREM2KO mice. At the age of 16 months, the mice were euthanized for tissue collection. ELISA was utilized for the assessment of Aβ40 and Aβ42 levels in brain tissue homogenates, and histochemical and immunohistochemical or immunofluorescent assays were used to evaluate amyloid deposition, astrogliosis, and microgliosis. All results were analyzed using GraphPad Prism 9. Results: TREM2 deficiency markedly increased overall Aβ load in SwDI/TREM2KO mice compared to SwDI/TREM2WT or SwDI/TREM2Het in the cortex, hippocampus, and thalamus. Intriguingly, TREM2 deletion led to a dramatic decrease in CAA in vasculature-enriched regions, such as thalamus, along with reduced microglial association with CAA. Consistent with previous reports, Aβ plaque-associated microglia were significantly reduced in SwDI/TREM2KO mice. Additional experiments are underway to explore the molecular mechanisms underlying the distinct impact of TREM2 deficiency on Aβ plaques and CAA. Conclusion: Deletion of TREM2 increases the overall brain Aβ load whereas decreases CAA, suggesting the differential role of TREM2 in the regulation of parenchymal versus vascular deposition of Aβ in the brain.