Dietary High-Fat Promotes Cognitive Impairment by Suppressing Mitophagy

Dietary habits contribute to the characteristics of Alzheimer's disease (AD) and cognitive impairment, which are partly induced by the accumulation of hyperphosphorylated Tau, a microtubule-associated protein. In mice, a fat-rich diet facilitates cognitive dysfunction. However, the mechanism by which dietary fat damages the brain remains unclear. In this study, 13-month-old C57BL/6 mice were fed a normal or high-fat diet (HFD) for 6 months. Neuro-2a cells were incubated with the normal medium or palmitic acid (200 μM). Spatial memory was assessed utilizing a behavioral test. Further, western blotting and immunofluorescence techniques were used to determine the levels of mitophagy-related proteins. The synaptic morphology and phosphorylation of Tau proteins were also evaluated. Administration of HFD decreased the expression of synaptophysin and brain-derived neurotrophic factor expression, leading to significant damage to neurons. Tau protein hyperphosphorylation was detected at different loci both in vivo and in vitro. Significantly impaired learning and memory abilities, accompanied by impaired mitophagy-related processes, were observed in mice fed with HFD as compared to mice fed with normal food. In conclusion, high fatty-acid intake hinders mitophagy and upregulates Tau protein phosphorylation, including age-related synaptic dysfunction, which leads to cognitive decline.