Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in Neuroscience, The University of British Columbia, Vancouver, Canada.
PLoS One. 2013 Jul 23;8(7):e69824. doi: 10.1371/journal.pone.0069824. Print 2013.
Abnormal deposition of neuriticplaques is the uniqueneuropathological hallmark of Alzheimer's disease (AD).Amyloid β protein (Aβ), the major component of plaques, is generated from sequential cleavage of amyloidβ precursor protein (APP) by β-secretase and γ-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 Aβ generation remains elusive. In this study, we investigated the effect of high glucose on APP metabolism and Aβ 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 Aβ 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 Aβ production. More importantly, the elevation of APP level and Aβ 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 withDMand suggests thatglycemic control might be potentially beneficial for reducing the incidence of AD in diabetic patients and delaying the AD progression.
神经原纤维缠结的异常沉积是阿尔茨海默病（AD）的独特神经病理学特征。淀粉样β蛋白（Aβ）是斑块的主要成分，由β-分泌酶和γ-分泌酶复合物对淀粉样β前体蛋白（APP）的连续切割产生。患有糖尿病（DM）的患者以慢性高血糖为特征，AD 发病风险增加。然而，高血糖在 APP 加工和 Aβ产生中的作用仍不清楚。在这项研究中，我们研究了高葡萄糖对培养的人细胞中 APP 代谢和 Aβ产生的影响。我们发现，高葡萄糖处理显著增加了神经元样和非神经元细胞中 APP 蛋白水平，并促进了 Aβ的产生。此外，我们发现高葡萄糖诱导的 APP 水平增加不是由于 APP 基因转录的增强，而是由于 APP 蛋白降解的抑制。总之，我们的数据表明，高血糖可能通过抑制 APP 降解和增强 Aβ产生来促进 AD 的发病机制。更重要的是，高葡萄糖引起的 APP 水平和 Aβ生成的增加是由于 APP 周转率的降低所致。因此，我们的研究提供了 DM 患者 AD 发病风险增加的分子机制，并表明血糖控制可能有助于降低糖尿病患者 AD 的发病率并延缓 AD 的进展。
