Age-related hyperinsulinemia leads to insulin resistance in neurons and cell-cycle-induced senescence
Age-related hyperinsulinemia leads to insulin resistance in neurons and cell-cycle-induced senescence
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年龄相关的高胰岛素血症导致神经元胰岛素抵抗和细胞周期诱导的衰老
DOI：
10.1038/s41593-019-0505-1
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发表时间：
2019-11-01
影响因子：
25
通讯作者：
Herrup, Karl
中科院分区：
文献类型：
--
作者：
Chow, Hei-Man;Shi, Meng;Herrup, Karl
前驱糖尿病和阿尔茨海默病的患病率都随着年龄的增长而增加。前者是后者的一个风险因素，但两者之间的机械联系仍然难以捉摸。我们发现，糖尿病前期血清高胰岛素血症反映在脑脊液中，这种长期升高的胰岛素使神经元对胰岛素抵抗。这导致异常的电生理活动和其他缺陷。此外，神经胰岛素抵抗减少己糖激酶2，从而损害糖酵解。这阻碍了p35的泛素化和降解，有利于其裂解为p25，从而过度激活CDK 5并干扰GSK 3 β诱导的β-连环蛋白降解。CDK 5导致神经元细胞死亡，而β-连环蛋白进入神经元细胞核并重新激活细胞周期机制。无法成功分裂，神经元反而进入衰老样状态。这些发现提供了外周高胰岛素血症之间的直接联系，如糖尿病前期，年龄相关的神经退行性变和认知能力下降。神经退行性疾病，如阿尔茨海默氏病的影响。
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 GSK3 beta-induced degradation of beta-catenin. CDK5 contributes to neuronal cell death while beta-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 between peripheral hyperinsulinemia, as found in prediabetes, age-related neurodegeneration and cognitive decline. The implications for neurodegenerative conditions such as Alzheimer's disease are described.