High glucose-mediated VPS26a down-regulation dysregulates neuronal amyloid precursor protein processing and tau phosphorylation.

Abstract

The relationship between hyperglycaemia-induced retromer dysfunction impairing intracellular trafficking and Alzheimer's disease (AD) remains unclear, although diabetes mellitus (DM) is considered a risk factor for AD. Here, we investigated the effects of high glucose on the retromer and defined the dysregulation of mechanisms of amyloid precursor protein (APP) processing and tau phosphorylation. We used human induced-pluripotent stem cell-derived neuronal differentiated cells and SH-SY5Ys exposed to high glucose to identify the underlying mechanisms. Streptozotocin-induced diabetic mice were used to elucidate whether the retromer contributes to the AD-like pathology. We found that vacuolar protein sorting-associated protein 26a (VPS26a) was decreased in the hippocampus of diabetic mice and high glucose-treated human neuronal cells. High glucose down-regulated VPS26a through ROS/NF-κB/DNA methyltransferase1-mediated promoter hypermethylation. VPS26a recovery blocked retention of APP and cation-independent mannose-6-phosphate receptor in endosomes and promoted transport to the trans-Golgi, which decreased Aβ levels, and improved cathepsin D activity, reducing p-tau levels, respectively. Retromer enhancement ameliorated synaptic deficits, astrocyte over-activation, and cognitive impairment in diabetic mice. In conclusion, VPS26a is a promising candidate for the inhibition of DM-associated AD pathogenesis by modulating APP processing and tau phosphorylation.