Aflatoxin B1-induced lipid disturbance and neuroinflammation contribute to Alzheimer's disease-like neuropathology in C57BL/6J mice

Aflatoxin B₁ (AFB₁) is a ubiquitous foodborne mycotoxin that has been associated with cognitive decline. In this study, we investigated the neuropathology linked to Alzheimer's disease (AD) caused by AFB₁ and revealed the underlying mechanism. Here, C57BL/6 J mice received AFB₁ (1.5 mg/L in drinking water) for 8 weeks. Behavioral tests, including Morris water maze and Y-maze, were conducted alongside hippocampal histology and immunostaining to detect cognitive deficits and hippocampal neuronal impairment. Non-targeted lipidomics was also employed to dissect alterations in the hippocampal lipid profile. Furthermore, dysregulation of the lipid-driven inflammatory response was confirmed by gene and protein assays for lipid metabolism and inflammatory signaling, as well as serum cytokine measurements. Results showed that AFB₁ impaired spatial learning and memory, caused hippocampal neuronal loss and increased App and phosphorylated Tau. Non-targeted lipidomics revealed that the AFB₁ exposure led to derangements in glycerophospholipid metabolism and increased the abundance of pro-inflammatory phosphatidylcholine (PC) species. Concurrently, the Tlr4/NF-κB cascade contributed to the enhanced systemic and hippocampal pro-inflammatory cytokine responses. Taken together, these results indicate that exposure to a low dose of AFB₁ results in an increase in pro-inflammatory PC species and hippocampal neuroinflammation via the Tlr4/NF-κB axis and hence contribute to the development of AD-like neuropathology. This highlights the therapeutic significance of targeting dysregulated lipid metabolism to counteract AFB₁-induced neurotoxicity in relation to AD.