Apolipoprotein receptor 2 and X11 alpha/beta mediate apolipoprotein E-induced endocytosis of amyloid-beta precursor protein and beta-secretase, leading to amyloid-beta production.
The homeostasis of amyloid-beta (Abeta) in the brain is critical to the pathogenesis of Alzheimer's disease (AD). Abeta 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 Abeta. The molecular mechanism by which neurons trigger the production of Abeta 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 Abeta. This mechanism, mediated by adaptor protein X11alpha or X11beta (X11alpha/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 Abeta 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 Abeta production, which may be important for the regulation of neuronal activity.
He
Xiangyuan
X
Protein Studies Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
Cooley
Kathleen
K
Chung
Charlotte H Y
CH
Dashti
Nassrin
N
Tang
Jordan
J
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015820:Cadherins; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002417:Cattle; D045744:Cell Line, Tumor; D004705:Endocytosis / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000502:physiology*; D000091042:Reelin Protein
C079091:APBA1 protein, human; C491636:APBA2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D015820:Cadherins; D002352:Carrier Proteins; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins; D018110:Receptors, Lipoprotein; D000091042:Reelin Protein; C098773:low density lipoprotein receptor-related protein 8; D053829:Amyloid Precursor Protein Secretases; C000717127:RELN protein, human; C000717128:Reln protein, mouse