TREM2 bridges microglia and extracellular microenvironment: Mechanistic landscape and therapeutical prospects on Alzheimer's disease.

Neuroinflammation is closely related to the pathogenesis of Alzheimer's disease (AD). One of its prominent cellular components, microglia, is a potent coordinator of neuroinflammation in interplay with the characteristic AD pathological alterations including Aβ, tau, and neuronal defects, which constitute the AD-unique extracellular microenvironment. Mounting evidence implicates Triggering Receptors Expressed on Myeloid Cells 2 (TREM2) in the center of microglial activation, a vital event in the pathogenesis of AD. TREM2 is a pivotal microglial receptor that interacts with specific elements present in the AD microenvironment and induces microglial intracellular signallings contributing to phagocytosis, migration, cytokine production, metabolism, and survival, which shapes the microglial activation profile. It follows that TREM2 builds up a bridge between microglia and the extracellular microenvironment. This review illustrates how TREM2 modulates microglia to affect AD pathogenesis. Mainly presented facets in the review are i. the development of AD-specific microglial phenotypes (disease-associated microglia, DAM), ii. microglial interactions with major AD pathologies, and iii. the underlying intracellular signallings of microglial activation. Also, outstanding controversies regarding the nature of neuroinflammation are discussed. Through our illustration, we attempt to establish a TREM2-centered network of AD pathogenesis, in the hope as well to provide insights into the potential therapeutic strategies based on the underlying mechanisms.