A novel TREM2 L15Q in signal peptide domain and its influence on Aβ pathogenicity

The triggering receptor expressed on myeloid cells 2 ( TREM2 ) gene is an important risk factor in Alzheimer’s disease (AD). The signal peptide (SP) domain plays a critical role in protein secretion and localization, however, its pathogenic variant remains unclear. This study investigated the novel L15Q mutation in the TREM2 SP domain and its effect on AD pathology. A novel TREM2 L15Q variant was identified from a 71-year-old patient, predicting the structural and functional disruptions. To examine its impact, HEK 293 cells were transfected. Glycosylation analysis revealed a distinct doublet of immature TREM2 bands in L15Q cells, both of which shifted upon PNGase F and Endo H treatments, confirming abnormal N-linked glycosylation. Quantifications revealed a reduced mature-to-immature ratio and decreased soluble TREM2 , suggesting impaired protein maturation. These findings demonstrated that the L15Q mutation in the SP domain disrupted the TREM2 glycosylation, maturation and secretion. Additionally, TREM2 L15Q cells reduced Aβ phagocytosis, elevated extracellular Aβ 42 and the Aβ 42/40 ratio, and decreased endogenous Aβ 42 levels, indicating the impaired Aβ clearance. Collectively, our results supported the crucial role of the TREM2 SP domain in maintaining protein functions and Aβ homeostasis, offering new insight into TREM2 -linked AD pathogenesis.