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[摘要]：Allelic variation in the apolipoprotein E (APOE) gene is the major risk factor of sporadic Alzheimer disease. ApoE is the primary cholesterol carrier in the brain. Previously, we demonstrated that intracellular degradation of beta-amyloid (A beta) peptides by microglia is dramatically enhanced in the presence of apoE. However, the molecular mechanisms subserving this effect remain unknown. This study reports a mechanistic link between apoE-regulated cholesterol homeostasis and A beta degradation. We demonstrate that promoting intracellular A beta degradation by microglia is a common feature of HDL apolipoproteins, including apoE and apoA-I. This effect was not dependent on the direct interaction of apoE and A beta. Regulation of A beta degradation was achieved by solely manipulating cellular cholesterol levels. The expression and the activity of A beta degrading enzymes, however, were not regulated by cholesterol. We observed that reducing cellular cholesterol levels by apoE resulted in faster delivery of A beta to lysosomes and enhanced degradation. Moreover, apoE facilitated the recycling of Rab7, a small GTPase responsible for recruiting the motor complex to late endosomes/lysosomes. These data indicate that faster endocytic trafficking of A beta-containing vesicles in the presence of apoE resulted from efficient recycling of Rab7 from lysosomes to early endosomes. Thus, apoE-induced intracellular A beta degradation is mediated by the cholesterol efflux function of apoE, which lowers cellular cholesterol levels and subsequently facilitates the intracellular-trafficking of A beta to lysosomes for degradation. These findings demonstrate a direct role of cholesterol in the intracellular A beta degradation. |
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