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.

中文翻译：

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AD发病机制中的TREM2：脂质代谢调节剂和潜在的代谢治疗靶点

髓细胞上表达的触发受体 2 (TREM2) 是一种单程跨膜免疫受体，主要在大脑中的小胶质细胞和外周的巨噬细胞上表达。最近的研究已将 TREM2 确定为阿尔茨海默病 (AD) 的危险因素。越来越多的证据表明，TREM2 可以影响中枢神经系统 (CNS) 和外周的脂质代谢。在中枢神经系统中，TREM2 影响胆固醇、髓磷脂和磷脂的代谢，并促进小胶质细胞转变为疾病相关表型。在外周，TREM2 通过调节肥胖及其并发症（如高胆固醇血症、动脉粥样硬化和非酒精性脂肪肝疾病）的发生和进展来影响脂质代谢。所有这些改变的脂质代谢过程都可能通过多种方式影响 AD 的发病机制，包括影响炎症、胰岛素抵抗和 AD 病理。在这里，我们将讨论 TREM2 介导脂质代谢以影响 CNS 和外周 AD 发病机制的潜在途径。此外，我们讨论了 TREM2 可能是在包括 AD 在内的疾病条件下连接中枢和外周脂质代谢的关键因素的可能性。这种联系可能是由于对血脑屏障完整性的影响，我们介绍了 TREM2 影响血脑屏障的潜在途径。此外，我们讨论了脂质在 TREM2 相关 AD 治疗中的作用。我们提出了一些针对 TREM2 的潜在疗法，并讨论了这些疗法的前景和局限性。