Fig. 3

Possible mechanisms by which chronic exercise improves AD lipid metabolism. Free fatty acids (FFAs) cross the BBB and provide an energy substrate for neurons and glial cells. FFAs are converted to cholesterol on the endoplasmic reticulum and bound to LXR/RXR to form LXR/RXR-Cholesterol complexes. Exercise activates the LXR/RXR pathway to increase ABCA1/ABCG1 and APOE expression in astrocytes and mediates cholesterol efflux into the extracellular fluids, promotes APOE lipidation by FFA, and stimulates Aβ degradation by NEP. Lipidated APOE is carried to neurons where the receptor (LDLR/LRP1) removes APOE from lipids and releases FFA into neurons, where it is further involved in neuronal cholesterol metabolism [120]. APOE binds to cholesterol to form APOE-cholesterol particles, which are subsequently mediated by LDLR/LRP1 into neurons and are dissociated. 1% cholesterol is converted into lipid droplets. Most of the cholesterol is catalyzed by enzymes to produce 24-hydroxycholesterol (24-OHC), which subsequently crosses the BBB into the plasma, while plasma 27-OHC flows through the BBB into the brain. A small amount of cholesterol is transported via ABCA1/ABCG1-mediated efflux to the extracellular fluid to form APOA1-Cholesterol particles with APOA1, which are subsequently transported to the blood via receptors. 27-OHC promotes APP cleavage to Aβ, while 24-OHC inhibits the amyloid pathway of Aβ [100]. In addition, Aβ can form an APOE-Aβ complex with APOE, which is attached to the surface of microglia via LDLR/LRP1 and Heparan sulfate proteoglycan (HSPG), and subsequently promotes the uptake and degradation of Aβ via endocytosis of microglia [121]