Abstract
Amyloid precursor protein (APP) at the plasma membrane is internalized via endocytosis and delivered to endo/lysosomes, where neurotoxic amyloid-β (Aβ) is produced via β-, γ-secretases. Hence, endocytosis plays a key role in the processing of APP and subsequent Aβ generation. β-, γ-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 nonraft-localized APP. In addition, APP endocytosis from lipid rafts was regulated by cholesterol levels. Our results demonstrate for the first time 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 Alzheimer’s disease.
Highlights
Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disease which is the most prevalent form of dementia [1]
We previously showed that cellular cholesterol level in Chinese hamster ovary (CHO) PS1
WT cells increased the rate of amyloid precursor protein (APP) endocytosis. These results suggest that cholesterol levels regulated APP endocytosis
Summary
Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disease which is the most prevalent form of dementia [1]. The hallmarks of AD pathogenesis are the extracellular deposition of senile plaques and the presence of intracellular neurofibrillary tangles, which lead to severe neuronal atrophy and death. Elevated levels and accumulation of cerebral β-amyloid (Aβ) peptides are the dominant pathological factor in the formation of senile plaques. Aβ is a byproduct of the sequential proteolytic cleavage of amyloid precursor protein (APP) by membrane bound βand γ-secretases [2,3,4]. APP at the plasma membrane is internalized via endocytosis and delivered to early endosomes and lysosomes, where Aβ is produced. APP is more likely to become accessible to β- and γ-secretases when the rate of APP endocytosis is increased, resulting in elevated production of Aβ [5,6]. The regulation of endocytic pathways plays a key role in the trafficking and processing of APP and subsequent Aβ generation
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