Long‐Term High‐Fat Diet Consumption Aggravates β‐Amyloid Deposition and Tau Pathology Accompanied by Microglial Activation in an Alzheimer's Disease Model

Abstract Alzheimer's disease (AD) is the most prevailing form of dementia, with long‐term high‐fat diet (HFD) consumption being a pivotal contributor to AD pathogenesis. As microglial dysfunction is a crucial factor in the AD onset, it becomes imperative to explore the effects of HFD on microglial function and AD pathogenesis. In the present study, 3xTg‐AD model mice at the age of 9‐month are subjected to random allocation, with one group receiving a standard diet (ND) and the other an HFD for 3 months. Subsequently, transcriptomic profiling of microglia unveils that HFD alters fatty acid metabolism and mediates T cell infiltration. Within the hippocampus, microglia exhibit aberrant morphology and lipid accretion in response to the HFD, evidenced by conspicuously enlarged microglial cell bodies and accumulation of lipid droplets. These lipid‐droplet‐accumulating microglia exhibit diminished migratory capacity and compromise plaque consolidation, thereby exacerbating the accumulation of β‐amyloid. Noteworthy, the HFD induces T cell infiltration, thereby aggravating neuroinflammation and Tau phosphorylation. Morris water maze test reveals that HFD‐consuming mice display marked impairment in memory performance. In summary, this study demonstrates that prolonged HFD consumption exacerbates amyloid deposition, tau pathology, and cognitive deficits, which is associated with the accumulation of lipid droplets within microglia.