Targeting hepcidin improves cognitive impairment and reduces iron deposition in a diabetic rat model

Cognitive impairment is a common complication of type 2 diabetes mellitus (T2DM) that may be related to iron deposition in the brain. Hepcidin is expressed in the brain and has the ability to regulate iron. Therefore, this study explored the role of hepcidin in hippocampal iron deposition and cognitive impairment in T2DM. The effects of a recombinant adeno-associated virus targeting hepcidin (AAV-hepcidin) for hippocampal iron content and cognitive function were investigated in a T2DM rat model induced by streptozotocin and a high-fat diet. Adult male rats (n = 32) were categorized as either C-saline (normal control), M-saline (T2DM), M-blank (AAV-blank + T2DM), or M-hepcidin (AAV-hepcidin + T2DM). Hippocampal iron content was assessed using quantitative susceptibility mapping. Morris water maze (MWM) testing was used to assess the cognitive function. Magnetic resonance imaging indicated that hippocampal susceptibility values were significantly increased bilaterally in T2DM rats compared with controls (P = 0.044, P = 0.043). Compared with the M-blank group, the M-hepcidin group exhibited significantly decreased hippocampal susceptibility values bilaterally (P = 0.007, P = 0.030). Compared with the M-saline group, susceptibility values from left hippocampus in the M-hepcidin group were significantly reduced (P = 0.002). MWM results showed that the performance of T2DM rats was significantly decreased from that of control rats. Compared with the M-saline and M-blank groups, the performance of the M-hepcidin group was significantly increased. These studies demonstrate that T2DM rats developed cognitive impairment and iron deposits in the hippocampus, both of which were improved by AAV-hepcidin administration.