Preferred endocytosis of amyloid precursor protein from cholesterol-enriched lipid raft microdomains

Amyloid precursor protein (APP) at the plasma membrane is internalized via endocytosis, and delivered to endosomes and lysosomes, where neurotoxic amyloid-{beta} (A{beta}) is produced via {beta}-, {gamma}-secretases. Hence, endocytosis plays a key role in the processing of APP and subsequent A{beta} generation. {beta}-, {gamma}-secretases as well as APP are localized in cholesterol-enriched lipid raft microdomains. However, it is still unclear whether lipid rafts are the site where APP undergoes endocytosis and whether cholesterol levels affect this process. In this study, we found that localization of APP in lipid rafts was increased by elevated cholesterol level. We also showed that increasing or decreasing cholesterol levels increased or decreased APP endocytosis, respectively. When we labeled cell surface APP, APP localized in lipid rafts preferentially underwent endocytosis compared to non-raft localized APP. In addition, APP endocytosis from lipid rafts was regulated by cholesterol levels. Our results indicate that cholesterol levels regulate the localization of APP in lipid rafts affecting raft-dependent APP endocytosis. Thus, regulating the microdomain localization of APP could offer a new therapeutic strategy for Alzheimers disease.