Apelin‐13 Alleviates Diabetes‐Associated Cognitive Decline by Reducing Oxidative Stress and Mitochondrial Dysfunction via the SIRT3/Foxo3 Pathway

The incidence of diabetes-related cognitive dysfunction is on the rise, yet clinical interventions to prevent this condition remain limited. Apelin-13, an endogenous peptide known for its positive inotropic and vasoactive properties, has been shown to exert diverse effects across various tissues and cell types. However, its potential protective role in diabetes-associated cognitive decline (DACD) remains poorly understood. To investigate this, we established a rodent diabetes model using a high-fat diet (HFD) combined with streptozotocin (STZ, intraperitoneal injection, 60 mg/kg). Cognitive function was evaluated using the Morris water maze and Y-maze tests. Additionally, we employed a range of techniques, including intraperitoneal glucose tolerance tests (IPGTT), insulin tolerance tests (ITT), immunofluorescence labeling, real-time PCR, Western blot analysis, and enzyme-linked immunosorbent assays (ELISA). Our results demonstrate that apelin-13 administration alleviated diabetes symptoms in the diabetic mouse model. Specifically, apelin-13 improved cognitive performance in both the Y-maze and Morris water maze tests. In the hippocampus of treated mice, apelin-13 reduced oxidative stress by enhancing the activity of superoxide dismutase (SOD) and catalase (CAT), while decreasing levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). Furthermore, apelin-13 improved mitochondrial function in the hippocampus by restoring the activities of COX I and COX IV (but not COX II) and increasing ATP production. Apelin-13 also restored SIRT3 expression and elevated the NAD+/NADH ratio in the hippocampus. As a result, apelin-13 facilitated the deacetylation and nuclear translocation of Foxo3a in the hippocampus. When SIRT3 was silenced, the beneficial effects of apelin-13 on oxidative stress, mitochondrial function, and cognitive impairment in diabetic mice were significantly diminished, underscoring the critical role of SIRT3 in these processes. In summary, our findings suggest that apelin-13 mitigates DACD by reducing oxidative stress and mitochondrial dysfunction through the SIRT3/Foxo3 pathway. These results highlight apelin-13 as a promising therapeutic candidate for DACD.