Abstract
Type 2 diabetes (T2D) is a high-risk factor for Alzheimer’s disease (AD) due to impaired insulin signaling pathway in brain. Capsaicin is a specific transient receptor potential vanilloid 1 (TRPV1) agonist which was proved to ameliorate insulin resistance. In this study, we investigated whether dietary capsaicin could reduce the risk of AD in T2D. T2D rats were fed with capsaicin-containing high fat (HF) diet for 10 consecutive days (T2D+CAP). Pair-fed T2D rats (T2D+PF) fed with the HF-diet of average dose of T2D+CAP group were included to control for the effects of reduced food intake and body weight. Capsaicin-containing standard chow was also introduced to non-diabetic rats (NC+CAP). Blood glucose and insulin were monitored. The phosphorylation level of tau at individual sites, the activities of phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) and glycogen synthase kinase-3β (GSK-3β) were analyzed by Western blots. The results revealed that the levels of phosphorylated tau protein at sites Ser199, Ser202 and Ser396 in hippocampus of T2D+CAP group were decreased significantly, but these phospho-sites in T2D+PF group didn’t show such improvements compared with T2D group. There were almost no changes in non-diabetic rats on capsaicin diet (NC+CAP) compared with the non-diabetic rats with normal chow (NC). Increased activity of PI3K/AKT and decreased activity of GSK-3β were detected in hippocampus of T2D+CAP group compared with T2D group, and these changes did not show in T2D+PF group either. These results demonstrated that dietary capsaicin appears to prevent the hyperphosphorylation of AD-associated tau protein by increasing the activity of PI3K/AKT and inhibiting GSK-3β in hippocampus of T2D rats, which supported that dietary capsaicin might have a potential use for the prevention of AD in T2D.
Highlights
Phosphorylation of tau on Ser396 was suggested to be a key step in the development of neurofibrillary pathology in Alzheimer’s disease brain [28]. When we compared these two kinases between normal chow (NC) and Type 2 diabetes (T2D) rats, we found that phosphorylation of both AKT and glycogen synthase kinase-3β (GSK-3β) was significantly lower in T2D rat brains than NC group, whereas the total levels of these two kinases were unchanged (Fig 4)
We found that short term intervention of dietary capsaicin, a highly selective agonist for transient receptor potential vanilloid 1 (TRPV1), increased insulin signaling pathway in hippocampus, which leads to inhibition of GSK-3β, prevention of hyperphosphorylation of tau protein and improved glucose metabolism and insulin resistance without affecting body weight in a rat model of type 2 diabetes
These findings provide novel insights into the possible mechanism by which lifestyle intervention of dietary capsaicin may be useful for preventing Alzheimer’s disease (AD) in type 2 diabetic patients
Summary
When compared with T2D group, capsaicin produced significant reductions in blood glucose, plasma insulin and HOMA-IR after 10 days of administration in T2D+PF group. No significant changes of blood glucose, plasma insulin and HOMA-IR between NC +CAP and NC groups after capsaicin exposure, which suggested no effects of capsaicin on glucose metabolism and insulin resistance on normal diet condition.
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