Decreased expression of protein O-linked mannose β-1,2-N- acetylglucosaminyltransferase 1 contributes to Alzheimer's disease-like pathologies

Alzheimer's disease (AD) is pathologically characterized by senile plaques and neurofibrillary tangles composed of beta-amyloid peptide (A beta) and tau hyperphosphorylation, respectively. Mannosylation, a particular type of posttranslational modification, may be involved in the pathogenesis of AD. However, its underlying mechanism remains unclear. Protein O-linked mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) catalyzes the formation of the N-acetylglucosamine beta-1,2-Man linkage of O-mannosylglycan, which can increase the protein posttranslational mannosylation level. The defective POMGnT1 gene leads to the hypomannosylation of proteins, which may cause cognitive decline in aged people. This study aimed to investigate whether POMGnT1 participated in the pathogenesis of AD and explore its underlying role using AD mouse and cell models. In this study, the expression of POMGnT1 was measured in AD models [beta-amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice, an AD mouse model; N2a cells stably transfected with Swedish mutant APP (N2a/APP), an AD cell model]. The results revealed that the expression of POMGnT1 decreased in AD mouse and cell models. In addition, POMGnTI-overexpressing N2a/APP cells were built by retroviral transfection. POMGnT1 overexpression may lower A beta levels by reducing APP production and downregulating beta- and gamma-secretase activities. It also promoted clearance of A beta by upregulating insulin-degrading enzymes and ameliorated tau hyperphosphorylation. Hence, it was concluded that POMGnT1 was involved in the pathogenic process of AD. The decreased expression of POMGnT1 contributes to AD-like pathologies. NEW & NOTEWORTHY This study explored the role of mannosylation in the pathogenesis of AD through a mannosyltransferase-POMGnT1. Results demonstrated that target gene overexpression could ameliorate pathologies of A beta and tau hyperphosphorylation. This study is the first to examine the relationship between mannosylation and AD.