Fig. 4

TREM2 is a regulator that links lipid metabolism in the CNS and the periphery. In the CNS, TREM2 promotes the microglial metabolism of cholesterol and PIP2 in a PLCγ2-associated way. TREM2 mediates the microglial response to myelin damage and promotes the microglial transition to DAM. In the periphery, TREM2-expressing macrophages can influence metabolic comorbidities of AD, such as obesity, atherosclerosis, and NAFLD. Therefore, the dysfunction of TREM2 leads to dysregulated lipid metabolism and induces inflammation and IR. Peripheral inflammation and IR eventually lead to neuroinflammation and IR in the CNS. In addition, the elevated sTREM2 levels in AD may cause BBB disruption. TREM2 may influence the integrity of the BBB by affecting inflammation, IR, the microglial oxidative response (releasing ROS), and C3 complement signaling. The damaged BBB allows for the increased passage of cholesterol and FFAs, therefore establishing an association between central and peripheral lipid metabolism