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

Abstract

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.