作者
Hei-Man Chow, Meng Shi, Aifang Cheng, Yuehong Gao, Guimiao Chen, Xuan Song, Raphaella Wai Lam So, Jie Zhang, Karl Herrup
发表日期
2019/11
期刊
Nature neuroscience
卷号
22
期号
11
页码范围
1806-1819
出版商
Nature Publishing Group US
简介
Prediabetes and Alzheimer’s disease both increase in prevalence with age. The former is a risk factor for the latter, but a mechanistic linkage between them remains elusive. We show that prediabetic serum hyperinsulinemia is reflected in the cerebrospinal fluid and that this chronically elevated insulin renders neurons resistant to insulin. This leads to abnormal electrophysiological activity and other defects. In addition, neuronal insulin resistance reduces hexokinase 2, thus impairing glycolysis. This hampers the ubiquitination and degradation of p35, favoring its cleavage to p25, which hyperactivates CDK5 and interferes with the GSK3β-induced degradation of β-catenin. CDK5 contributes to neuronal cell death while β-catenin enters the neuronal nucleus and re-activates the cell cycle machinery. Unable to successfully divide, the neuron instead enters a senescent-like state. These findings offer a direct connection …
学术搜索中的文章
HM Chow, M Shi, A Cheng, Y Gao, G Chen, X Song… - Nature neuroscience, 2019