Apolipoprotein receptor 2 and X11α/β mediate apolipoprotein E-induced endocytosis of amyloid-β precursor protein and β-secretase, leading to amyloid-β production

Abstract

The homeostasis of amyloid-β(Aβ) in the brain is critical to the pathogenesis of Alzheimer's disease (AD).Aβ is a fragment of amyloid-β precursor protein (APP) generated in neurons by two proteases, β- and γ-secretases. APP and β-secretase, both present on cell surface, are endocytosed into endosomes to produce Aβ. The molecular mechanism by which neurons trigger the production of Aβ is poorly understood. We describe here evidence that the binding of lipid-carrying apolipoprotein E (ApoE) to receptor apolipoprotein E receptor 2 (ApoER2) triggers the endocytosis of APP, β-secretase, and ApoER2 in neuroblastoma cells, leading to the production of Aβ. This mechanism, mediated by adaptor protein X11α or X11β (X11α/β), whose PTB (phosphotyrosine-binding) domain binds to APP and a newly recognized motif in the cytosolic domain of ApoER2. Isomorphic form ApoE4 triggers the production of more Aβ than by ApoE2 or ApoE3; thus, it may play a role in the genetic risk of ApoE4 for the sporadic AD. The mechanism, which functions independently from Reelin-ApoER2 interaction, also provides a link between lipid uptake and Aβ production, which may be important for the regulation of neuronal activity. Copyright © 2007 Society for Neuroscience.