TREM2 in the pathogenesis of AD: a lipid metabolism regulator and potential metabolic therapeutic target

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane immune receptor that is mainly expressed on microglia in the brain and macrophages in the periphery. Recent studies have identified TREM2 as a risk factor for Alzheimer's disease (AD). Increasing evidence has shown that TREM2 can affect lipid metabolism both in the central nervous system (CNS) and in the periphery. In the CNS, TREM2 affects the metabolism of cholesterol, myelin, and phospholipids and promotes the transition of microglia into a disease-associated phenotype. In the periphery, TREM2 influences lipid metabolism by regulating the onset and progression of obesity and its complications, such as hypercholesterolemia, atherosclerosis, and nonalcoholic fatty liver disease. All these altered lipid metabolism processes could influence the pathogenesis of AD through several means, including affecting inflammation, insulin resistance, and AD pathologies. Herein, we will discuss a potential pathway that TREM2 mediates lipid metabolism to influence the pathogenesis of AD in both the CNS and periphery. Moreover, we discuss the possibility that TREM2 may be a key factor that links central and peripheral lipid metabolism under disease conditions, including AD. This link may be due to impacts on the integrity of the blood-brain barrier, and we introduce potential pathways by which TREM2 affects the blood-brain barrier. Moreover, we discuss the role of lipids in TREM2-associated treatments for AD. We propose some potential therapies targeting TREM2 and discuss the prospect and limitations of these therapies.

Keywords: Alzheimer’s disease; Central nervous system; Lipid metabolism; Peripheral system; TREM2; Therapeutic target.

Fig. 1

TREM2 regulates microglial cholesterol metabolism and participates in the response to myelin damage. The activation of the TREM2-DAP12 signaling pathway may promote microglial cholesterol efflux and reduces intracellular cholesterol to be stored as CE, possibly by activating PLCγ2. The effluent cholesterol might be carried by APOE-containing lipoproteins. Besides, TREM2 mediates the microglial response to myelin damage, leading to increased phagocytosis of myelin debris and thus may promote remyelination.

Fig. 2

TREM2 promotes the microglial transition to DAM. TREM2 binds to NAMPs and then triggers the microglial transition to DAM (CD11c +). In mouse models, microglia deficient in either Trem2 or ApoE failed to convert to DAM. Pro-inflammatory and anti-inflammatory phenotypes have been identified in DAM. Pro-inflammatory DAM was characterized by surface marker CD44, while anti-inflammatory DAM expressed surface marker CXCR4. Both of these phenotypes occur downstream of Trem2, while the presence of pro-inflammatory DAM also requires the expression of Treml2

Fig. 3

Macrophages with a high expression of TREM2 influence the metabolic comorbidities of AD. After sensing peripheral microenvironmental stimuli, macrophages transit into different phenotypes, such as LAMs, TREM2 hi macrophages, and hepatic transitional macrophages. LAMs play a protective role in obesity through the formation of crown-like structures in adipose tissue. TREM2 hi macrophages increase lipid metabolism in atherosclerotic plaques, although they may reduce the stability of plaques. The hepatic transitional macrophages express high levels of TREM2 and can then transform into Kupffer cells to promote the repair of liver tissue damage and influence the pathogenesis of NAFLD. In addition, Trem2-deficient macrophages in the liver increase the synthesis of ceramides and release exosomes that could impair hepatocytic energy supply in NAFLD

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