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 M). 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 and . 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.