title: ApoER2 expression increases Abeta production while decreasing Amyloid Precursor Protein (APP) endocytosis: Possible role in the partitioning of APP into lipid rafts and in the regulation of gamma-secretase activity.
abstract: BACKGROUND
  The generation of the amyloid-beta peptide (Abeta) through the proteolytic processing of the amyloid precursor protein (APP) is a central event in the pathogenesis of Alzheimer's disease (AD). Recent studies highlight APP endocytosis and localization to lipid rafts as important events favoring amyloidogenic processing. However, the precise mechanisms underlying these events are poorly understood. ApoER2 is a member of the low density lipoprotein receptor (LDL-R) family exhibiting slow endocytosis rate and a significant association with lipid rafts. Despite the important neurophysiological roles described for ApoER2, little is known regarding how ApoER2 regulates APP trafficking and processing.
  
  
  RESULTS
  Here, we demonstrate that ApoER2 physically interacts and co-localizes with APP. Remarkably, we found that ApoER2 increases cell surface APP levels and APP association with lipid rafts. The increase of cell surface APP requires the presence of ApoER2 cytoplasmic domain and is a result of decreased APP internalization rate. Unexpectedly, ApoER2 expression correlated with a significant increase in Abeta production and reduced levels of APP-CTFs. The increased Abeta production was dependent on the integrity of the NPxY endocytosis motif of ApoER2. We also found that expression of ApoER2 increased APP association with lipid rafts and increased gamma-secretase activity, both of which might contribute to increased Abeta production.
  
  
  CONCLUSIONS
  These findings show that ApoER2 negatively affects APP internalization. However, ApoER2 expression stimulates Abeta production by shifting the proportion of APP from the non-rafts to the raft membrane domains, thereby promoting beta-secretase and gamma-secretase mediated amyloidogenic processing and also by incrementing the activity of gamma-secretase.
authors.affiliation: FONDAP Center for Cell Regulation and Pathology (CRCP), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile. fuentealba_r@kids.wustl.edu
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Fuentealba
authors.forename: Maria Ines
authors.initials: MI
authors.lastname: Barría
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Lee
authors.forename: Judy
authors.initials: J
authors.lastname: Cam
authors.forename: Claudia
authors.initials: C
authors.lastname: Araya
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Escudero
authors.forename: Nibaldo C
authors.initials: NC
authors.lastname: Inestrosa
authors.forename: Francisca C
authors.initials: FC
authors.lastname: Bronfman
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.forename: Maria-Paz
authors.initials: MP
authors.lastname: Marzolo