Apolipoprotein receptor 2 and X11 α/β mediate apolipoprotein E-induced endocytosis of amyloid-β precursor protein and β-secretase, leading to amyloid-β production

The homeostasis of amyloid-beta(A beta) in the brain is critical to the pathogenesis of Alzheimer's disease (AD). A beta is a fragment of amyloid-beta precursor protein (APP) generated in neurons by two proteases, beta- and gamma-secretases. APP and beta-secretase, both present on cell surface, are endocytosed into endosomes to produce A beta. The molecular mechanism by which neurons trigger the production of A beta 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, beta-secretase, and ApoER2 in neuroblastoma cells, leading to the production of A beta. This mechanism, mediated by adaptor protein XII alpha or XII beta (X11 alpha/beta), 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 A beta 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 A beta production, which may be important for the regulation of neuronal activity.