TREM2 in Neurodegenerative Disorders: Mutation Spectrum, Pathophysiology, and Therapeutic Targeting

TREM2 (triggering receptor expressed on myeloid cells 2) is a membrane-bound receptor primarily expressed on microglia in the central nervous system (CNS). TREM2 plays a crucial role in regulating immune responses, phagocytosis, lipid metabolism, and inflammation. Mutations in the TREM2 gene have been linked to various neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD), and Nasu–Hakola disease (NHD). These mutations are suggested to impair microglial activation and reduce the ability to clear amyloid aggregates, leading to exacerbated neuroinflammatory responses and accelerating disease progression. This review provides an overview of TREM2 structure, functions, and known pathogenic variants—including Arg47His, Arg62His, His157Tyr, Tyr38Cys, and Thr66Met. Furthermore, the molecular and cellular consequences of TREM2 mutations are introduced, such as impaired ligand binding, altered protein folding and trafficking, enhanced TREM2 shedding, and dysregulated inflammatory signaling. We also highlight recent advances in therapeutic strategies aimed at modulating TREM2 signaling. These include monoclonal antibodies (e.g., AL002, CGX101), small molecule agonists, and gene/cell-based therapies that seek to restore microglial homeostasis, enhance phagocytosis, and reduce neuroinflammation. While these approaches show promise in in vivo/in vitro studies, their clinical translation may be challenged by disease heterogeneity and mutation-specific responses. Additionally, determining the appropriate timing and precise dosing will be essential.