The connection between diabetes and Alzheimer’s disease (AD) is not fully determined. Hyperphosphorylation of tau protein is mediated by binding and stabilization of truncated p25 with cyclin-dependent kinase-5 (CDK5) in AD. We recently showed that diabetes-associated hyperglycemia increased the CDK5 levels to promote development of AD. Here, we examined the underlying mechanisms. Hyperglycemia and glucose intolerance were induced in rats that had received a low dose of streptozotocin (STZ) and a high fat diet (HFD). Compared to the control rats that received no STZ and normal diet-fed, the STZ + HFD rats exhibited poorer performance in the behavioral test and showed hyperacetylation of H3K9 histone on CDK5 promoter, likely resulting from upregulation of a histone acetyltransferase, GCN5. Inhibition of acetylation of H3K9 histone by a specific GCN5 inhibitor, MB3, attenuated activation of CDK5, resulting in decreased tau phosphorylation in rat brain and improved performance of the rats in the behavior test. Thus, these data suggest that diabetes may promote future development of AD through hyperacetylation of H3K9 histone on CDK5 promoter.

中文翻译：

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糖尿病诱导的 H3K9 高乙酰化通过 CDK5 促进阿尔茨海默病的发展。

糖尿病与阿尔茨海默病 (AD) 之间的联系尚未完全确定。tau 蛋白的过度磷酸化是由截短的 p25 与 AD 中细胞周期蛋白依赖性激酶 5 (CDK5) 的结合和稳定介导的。我们最近发现糖尿病相关的高血糖症会增加 CDK5 水平以促进 AD 的发展。在这里，我们检查了潜在的机制。在接受低剂量链脲佐菌素 (STZ) 和高脂肪饮食 (HFD) 的大鼠中诱发了高血糖症和葡萄糖耐受不良。与未接受 STZ 和正常饮食喂养的对照大鼠相比，STZ + HFD 大鼠在行为测试中表现出较差的表现，并且在 CDK5 启动子上表现出 H3K9 组蛋白的过度乙酰化，这可能是由于组蛋白乙酰转移酶 GCN5 的上调所致。通过特定的 GCN5 抑制剂 MB3 抑制 H3K9 组蛋白的乙酰化，减弱了 CDK5 的激活，导致大鼠脑中 tau 磷酸化降低，并改善了大鼠在行为测试中的表现。因此，这些数据表明糖尿病可能通过 CDK5 启动子上 H3K9 组蛋白的过度乙酰化促进 AD 的未来发展。