High Glucose Promotes Aβ Production by Inhibiting APP Degradation

Abnormal deposition of neuriticplaques is the uniqueneuropathological hallmark of Alzheimer's disease (AD). Amyloid beta protein (A beta), the major component of plaques, is generated from sequential cleavage of amyloidb precursor protein (APP) by beta-secretase and gamma-secretase complex. Patients with diabetes mellitus (DM), characterized by chronic hyperglycemia, have increased risk of AD development. However, the role of high blood glucose in APP processing and A beta generation remains elusive. In this study, we investigated the effect of high glucose on APP metabolism and A beta generation in cultured human cells. We found that high glucose treatment significantly increased APP protein level in both neuronal-like and non-neuronal cells, and promoted A beta generation. Furthermore, we found that high glucose-induced increase of APP level was not due to enhancement of APP gene transcription but resulted from inhibition of APP protein degradation. Taken together, our data indicated that hyperglycemia could promote AD pathogenesis by inhibiting APP degradation and enhancing A beta production. More importantly, the elevation of APP level and A beta generation by high glucose was caused by reduction of APP turnover rate. Thus, our study provides a molecular mechanism of increased risk of developing AD in patients with DM and suggests thatglycemic control might be potentially beneficial for reducing the incidence of AD in diabetic patients and delaying the AD progression.