Objective: Epidemiological studies have identified obesity as a risk factor for Alzheimer's disease (AD), however, evidence for molecular mechanisms is still insufficient. Microglia, the innate immune cells of the CNS, play a protective role by phagocytizing and clearing excess accumulated amyloid β (Aβ) protein in the AD brain. The metabolic pathway and functional activity of microglia affect each other, so our study aims to explore how high-fat diet (HFD) intake regulates microglia metabolism and function in the context of AD, to reveal the mechanism by which HFD induced obesity affects the AD progression at cellular level.
Methods: APPNL-G-F/NL-G-F AD model mice were fed a HFD to explore whether HFD intake accelerates the development of Aβ pathology. Then, we isolated microglia from the cerebral cortex and hippocampus of mice, and analyzed the expression of the phagocytosis-related receptor Trem2. In addition, we treated MG6 microglial cell line in vitro with fatty acids rich in HFD, and analyzed its phagocytic activity and Trem2 expression.
Results: Our results indicated that HFD intake not only accelerated Aβ pathology but also inhibited the recruitment of microglia to Aβ plaques. We also found that HFD ingestion and in vitro treatment of oleic acid, the most abundant fatty acid in HFD, aggravated intracellular lipid droplet accumulation and downregulated Trem2 expression as well as phagocytic activity of microglia.
Conclusion: HFD ingestion accelerates AD progression by affecting microglial lipid metabolism and blocking their protective functions.
Keywords: Alzheimer's disease; high-fat diet; lipid metabolism; microglia; phagocytosis