Claudia mori alzheimer9/18/2023 ![]() ![]() Several cell biology studies on APP metabolism have determined that this membrane protein undergoes two well-compartmentalized processing routes, the amyloidogenic and the non-amyloidogenic. Aβ peptide has well-established neurotoxic effects when aggregated into oligomeric and fibrillar states, usually seeded by the amyloid prone Aβ 42 species and is also able to interfere with synaptic function, a condition that probably commits neurons to cell death. The Aβ peptide, usually ranging from 40 to 43 amino acids in length, derives from the proteolytic processing of the amyloid precursor protein (APP) and has a central role in AD pathology. One of the pathological hallmarks of Alzheimer's disease (AD) is the presence of extracellular deposits of the amyloid beta (Aβ) protein. However, ApoER2 expression stimulates Aβ production by shifting the proportion of APP from the non-rafts to the raft membrane domains, thereby promoting β-secretase and γ-secretase mediated amyloidogenic processing and also by incrementing the activity of γ-secretase. These findings show that ApoER2 negatively affects APP internalization. We also found that expression of ApoER2 increased APP association with lipid rafts and increased γ-secretase activity, both of which might contribute to increased Aβ production. The increased Aβ production was dependent on the integrity of the NPxY endocytosis motif of ApoER2. Unexpectedly, ApoER2 expression correlated with a significant increase in Aβ production and reduced levels of APP-CTFs. The increase of cell surface APP requires the presence of ApoER2 cytoplasmic domain and is a result of decreased APP internalization rate. Remarkably, we found that ApoER2 increases cell surface APP levels and APP association with lipid rafts. Here, we demonstrate that ApoER2 physically interacts and co-localizes with APP. Despite the important neurophysiological roles described for ApoER2, little is known regarding how ApoER2 regulates APP trafficking and processing. ApoER2 is a member of the low density lipoprotein receptor (LDL-R) family exhibiting slow endocytosis rate and a significant association with lipid rafts. However, the precise mechanisms underlying these events are poorly understood. ![]() Recent studies highlight APP endocytosis and localization to lipid rafts as important events favoring amyloidogenic processing. The generation of the amyloid-β peptide (Aβ) through the proteolytic processing of the amyloid precursor protein (APP) is a central event in the pathogenesis of Alzheimer's disease (AD). ![]()
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