Hyperglycemia promotes Alzheimer's disease-like pathological changes by upregulating the CDK5 expression through AMPK/SIRT1 action

Abstract

Objective This study aims to elucidate the underlying mechanism of hyperglycemia induced Alzheimer's disease (AD)-like pathological changes. Methods Thirty Sprague Dawley rats (aged 18 weeks) were randomly divided into one control groups and two experimental groups (n=10 for each group), including control group, STZ+HFD group, and STZ+HFD+AICAR group. Control rats (n=10) was fed with the standard diet and experimental rats (n=20) was fed with high fat diet (HFD) for 8 weeks. 8 weeks after feeding, we estimated the reliability of the experimental model by measuring blood glucose levels (each week) of rats, serum insulin concentrations and oral glucose tolerance test (OGTT) test. Then experimental rats were injected with 50 mg/kg/ day Streptozotocin (STZ) intraperitoneally for three days, whereas the control rats were given the same dose of citric acid buffer for comparison. Morris water maze tests was performed to observe the functional changes of brain regions related to spatial learning and memory in each group. Western blot was performed to detect the abundances of AMPK, p-AMPK, SIRT1, H3acK9 and CDK5 in rats. Immunohistochemistry staining was performed to evaluate the levels of MAPT/Tau which can reflect the AD-like pathological changes. Furthermore, AMPK agonist (AICAR) was used to assess whether AMPK/SIRT1 pathway, which participate in the AD-like pathological changes, is the upstream molecules of H3acK9 and CDK5. Results We found treatment with HFD and STZ significantly increased blood glucose and serum insulin levels, and impaired glucose tolerance in rats. Hyperglycemia led to a decrease in the activity of AMPK and expression of SIRT1. The expression levels of underlying molecules of AMPK including H3acK9 and CDK5 significantly increased. The levels of phosphorylated Tau significantly increased in brain tissues. Additonally, AICAR administration partial reversed hyperglycemia-induced AD-like molecular pathologic changes through activating AMPK/SIRT1, decreasing expression of H3acK9 and CDK5, and inhibiting Tau protein hyperphosphorylation in rat brain tissues. Conclusion Hyperglycemia induces inactivation of AMPK/SIRT1 pathway which promotes excessive deacetylation of H3K9 and over expression of CDK5, these changes in turn lead to Tau protein hyperphosphorylation and AD-like molecular pathologic changes.

Keywords

• alzheimer's disease
• hyperglycemia
• ampk
• sirt1
• cdk5
• h3ack9