Dendrobine alleviates the T2D/AD comorbidity in 3xTg-AD mice feeding high-fat diet via the Cav-1/PERK/CHOP pathways.

BACKGROUND AND PURPOSE: Type 2 diabetes mellitus (T2D) exacerbates Alzheimer's disease (AD). Dendrobium nobile Lindl. alkaloids exhibited beneficial effects against T2D and/or AD. Dendrobine, a main alkaloid of Dendrobium nobile, against T2D/AD comorbidity was further examined in this study.

EXPERIMENTAL APPROACH: The T2D/AD comorbidity model was established by feeding 4-month-old 3 × Tg-AD mice with high-fat diet (HFD) for 8 months. Dendrobine was administered for 6 months after 2 months of high-fat diet feeding Blood glucose was monitored monthly and behavioral tests were conducted after 8-month of HFD. At the end of experiment, blood was collected for lipid profiling; pancreas and brain for histopathology, immunohistochemistry, and immunofluorescence. Hippocampal tissues were frozen for oxidative stress assays (ELISA) and protein analysis (Western blot).

KEY

RESULTS

Dendrobine ameliorated metabolic changes and pancreas damage, improved cognitive function and brain pathology in T2D/AD mice. It reduced oxidative damage in the pancreas and brain, as evidenced by Dihydroethidium staining and reduced ROS and reactive nitrogen species levels with increased antioxidant superoxide dismutase and glutathione S-transferase levels. Dendrobine increased insulin while decreased glucagon in pancreatic islet cells, but also increased insulin receptor expression in the brain, thus alleviating insulin resistance. T2D/AD comorbidity decreased Cav-1 in the pancreas and brain, accompanied by increased PERK and CHOP proteins to induce ER stress, which were ameliorated by Dendrobine in a dose-dependent manner.

CONCLUSION AND IMPLICATIONS: Dendrobine was effective in the protection against T2D/AD comorbidity. The mechanisms of protection could be attributed to reversed insulin resistance, reduced oxidative damage and ER stress through the Cav-1/PERK/CHOP pathways.