The effect of high glucose on APP metabolism and Abeta production

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by a progressive decline in memory and cognitive functions. It is the leading cause of dementia. Abnormal accumulation and deposition of amyloid-β protein (Aβ) to form plaques is a pathological hallmark of AD. Aβ, the major component of plaques, derives from sequential cleavage of amyloid-β precursor protein (APP) by β-secretase and γ-secretase. Dysregulation of APP processing and Aβ generation is believed to play an essential role in the pathogenesis of AD. Diabetes is a complex metabolic disorder characterized by chronic hyperglycemia. Epidemiological studies revealed an elevated risk of developing AD in people with diabetes. However, the underlying mechanisms remain unknown. To identify the role of diabetes in AD pathogenesis, the effect of high glucose on APP metabolism and Aβ generation was investigated using cultured human neuroblastoma cells. In this study, we clearly showed that high glucose treatment significantly increased APP protein level and Aβ generation. Moreover, the increase of APP level was not resulted from the enhancement APP gene transcription but due to the inhibition of APP protein degradation. This work indicated that hyperglycemia could promote AD development by increasing APP expression and facilitating APP processing and Aβ production, suggesting glycemic control might be beneficial for AD treatment.Medicine, Faculty ofGraduat

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