High-Fat Diet-Induced Excessive Accumulation of Cerebral Cholesterol Esters and Microglial Dysfunction Exacerbate Alzheimer's Disease Pathology in APP^NL−G−F mice

Epidemiological studies have identified high-fat diet (HFD)-induced obesity as a risk factor for Alzheimer's disease (AD), yet the underlying molecular mechanisms remain inadequately elucidated. Microglia, the brain’s innate immune cells, are pivotal in AD brain by engulfing β-amyloid (Aβ) peptides and compacting poorly consolidated Aβ plaques. Microglia are highly susceptible to the metabolic milieu; however, it is unclear how long-term HFD alters the lipid environment and influences microglial phenotype in AD brains. In this study, APP^NL−G−F knock-in AD model mice were fed an HFD for 9–27 weeks and subsequently analyzed for Aβ pathology and microglial function. Our findings indicated that HFD intake accelerated Aβ deposition, attenuated the recruitment of microglia to the plaques and impaired their phagocytic activity, while also promoting the accumulation of intracellular lipid droplets (LDs). Lipidomic analyses revealed that HFD, in synergy with AD pathology, increased the proportion of cholesterol esters in the cerebral cortex. In vitro, oleic acid—a major HFD constituent—similarly diminished the phagocytic capacity of MG6 microglia and induced LDs accumulation, along with downregulation of gene sets of cholesterol efflux, phagocytosis and engulfment. Overall, these findings implied that HFD-induced perturbation in brain cholesterol homeostasis may compromise microglial activation and expedite AD progression in APP^NL−G−F mice.