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

ABSTRACT 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.