Aflatoxin B1 exposure induces Alzheimer's disease like pathology by disrupting redox homeostasis and activating ferroptotic signals in C57BL/6 J mice

Abstract

Aflatoxin B1 (AFB1) is one of the most toxic mycotoxins with neurotoxicity. Human exposure to AFB1 via contaminated foodstuffs has been linked to the risk of cognitive impairment, which may contribute to the progression of Alzheimer's disease (AD). However, the mechanism underlying the pathogenesis of AD in relation to AFB1 exposure is not clear. Herein, C57BL/6 J mice were exposed to 1.5 mg/L AFB1 in drinking water for 8 weeks. It was found that AFB1 damaged blood-brain barrier function, accumulated in the brain, and led to cognitive impairments and AD-like pathology in the hippocampus. Impaired cognitive function was indicated by the significant alterations in Morris' water maze and Y-maze tests at 8 weeks after AFB1 exposure. Concurrently, AD-like pathology was evinced by a marked neuronal loss and the up-regulated AD related gene and protein expressions in the hippocampus. AFB1 exposure remarkably disrupted redox homeostasis and induced ferroptosis both in the hippocampus at 8 weeks after AFB1 exposure and in cultured hippocampal neuron in vitro as indicated by the suppressions on SOD and CAT activities, the down-regulation of Slc7a11/Gpx4 expressions, the decline in GSH content, the increase in MDA and the lipid peroxidation. AFB1 exposure also increased Fe²⁺ content significantly at 8 weeks after exposure. In addition, we demonstrated that ferroptosis inhibition by Fer-1 obviously alleviated AFB1 neurotoxicity in HT22 cells. These results revealed an unknown pivotal role of ferroptosis in AFB1 neurotoxicity in relation to AD pathogenesis and emphasized the importance to reduce the health risk of AFB1 exposure as an etiology of AD in humans.