Neuritin suppresses GABAergic neurons ferroptosis to improve cognitive impairment in diabetes mellitus

Abstract Aims: Alterations in iron homeostasis are associated with several neurodegenerative diseases. Cognitive dysfunction has become an important concomitant symptom in people with type 2 diabetes mellitus. Therefore, we investigated the role of neuritin in ameliorating cognitive dysfunction resulting from ferroptosis in diabetic neurons using a model of neuritin overexpression in GABAergic. Methods: The constructed transgenic mice were used to observe memory function changes using the Morris water maze. The ferroptosis in GABAergic in hippocampus and AMPK/Nrf2 signaling pathway were detected by Western blot, transmission electron microscopy, and immunofluorescence. High glucose was used to induce ferroptosis in HT22 cells in vitro, and neuritin was further confirmed to reduce ferroptosis in HT22 cells through AMPK/Nrf2 signaling pathway by chemical assays and Western blot assays. Results: Neuritin overexpression in GABAergic of db/db mice significantly ameliorated cognitive dysfunction, mitochondrial dysfunction, reversed ferroptosis-associated symbolic changes and reduced ferroptosis in the hippocampus. And also increased the co-localisation coefficient of GAD65 and AMPK in the hippocampus. Neuritin activates the AMPK/Nrf2 signaling pathway to inhibit high glucose induced ferroptosis in HT22 cells. Neuritin was observed to regulate the AMPK/Nrf2 signaling pathway in HT22 cells and promote Nrf2 expression to inhibit HT22 cell ferroptosis and ameliorate diabetic cognitive dysfunction. Conclusions: These findings suggest that neuritin may attenuate diabetes associated cognitive dysfunction by modulating neuronal ferroptosis, at least partly via AMPK/Nrf2 signaling pathway.