Aims:
Iron metabolism is involved in many biological processes in the brain. Alterations in
iron homeostasis have been associated with several
neurodegenerative disorders. Instead of
stroke and
ischemic heart disease,
dementia has become the second leading cause of mortality among the
type 2 diabetes mellitus (T2DM) population. Therefore, we attempted to investigate the role of ferroptosis in diabetes-associated
cognitive dysfunction (DACD). Results: We evaluated ferroptosis hallmarks in the hippocampus of T2DM (high-fat diet/
streptozotocin, HFD/STZ) mice, primary hippocampal neurons, as well as in the blood of patients. The results of Gene Set Enrichment Analysis showed significantly differentially expressed genes related to ferroptosis-related pathways between normal control (db/m) and
leptin receptor-deficient (db/db) mice. Here, ferroptosis,
mitochondrial dysfunction and
cognitive impairment were revealed, and
caveolin-1 (cav-1) was significantly downregulated in the hippocampus of T2DM (HFD/STZ) mice. In addition,
ferrostatin-1 and cav-1 restoration neutralized ferroptosis-related symbolic changes,
mitochondrial dysfunction, and improved
cognitive dysfunction. Notably, the plasma levels of Fe2+ and
4-hydroxynonenal (4-HNE) in T2DM patients showed a tendency to increase compared with those in nondiabetic subjects, and the Fe2+ level was negatively correlated with the cognitive ability in T2DM subjects. Innovation: For the first time, this study suggested that ferroptosis promoted the progression of DACD induced by T2DM both in vivo and in vitro, and supported the clinical evidence for the correlation between ferroptosis and T2DM-related DACD, which provided new insights into the potential
antioxidant effects of ferroptosis inhibitors and cav-1 on DACD. Conclusions: The overexpression of cav-1 may attenuate DACD by modulating neuronal ferroptosis-mediated mitochondrial homeostasis. We put cav-1 on the spotlight as a promising candidate to prevent DACD. Antioxid. Redox Signal. 37, 867-886.