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.