Abstract TP098: GLP-1 Agonist Improves VCID by Preventing Mitochondrial Dysgenesis in Diabetic Mice.

Our group has recently shown that the GLP-1 agonist improves vascular-induced cognitive impairment and dementia (VCID) in diabetic mice. Specifically, we demonstrated that the GLP-1 agonist, Exendin-4, reduced diabetes-induced cerebrovascular inflammation and oxidative stress, while improving vascular integrity. In the present study, we further investigate the molecular mechanism behind these protective effects. We investigated the effect of a GLP-1 agonist on mitochondrial dysgenesis (structure and function dysfunctions). We hypothesized that the neuroprotective effect of GLP-1 in diabetes is mediated, in part, through the preservation of mitochondrial structure and function. Methods: Diabetes was induced in male C57BL/6 mice using a high-fat diet combined with a low-dose streptozotocin injection. After confirmation of diabetes, mice were randomly assigned to receive either vehicle or Exendin-4 (30 ng/kg/day). After 8 weeks of treatment, tissue was collected, fixed, and examined using transmission electron microscopy (TEM). Mitochondrial structural parameters—including area, perimeter, length, and width—were quantified using ImageJ software. Mitochondrial function was assessed by slot blot analysis and immunohistochemistry. Results: Diabetes caused marked alterations in mitochondrial morphology, with significant reductions in area, perimeter, length, and width (P<0.05). Diabetes causes mitochondria to shrink with loss of integrity between the outer and inner membranes. Treatment with Exendin-4 significantly restored all parameters of mitochondrial morphology and membrane integrity (P<0.05). Furthermore, Exendin-4 improved mitochondrial function and reduced mitochondrial uncoupling (P<0.05). Conclusion: These findings underscore the vulnerability of mitochondrial structure to metabolic stress and highlight its role in the pathophysiology of neurovascular disorders. Moreover, our results provide novel evidence that GLP-1 agonists exert neurovascular protective effects, at least in part, by restoring mitochondrial integrity and function.