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The Journal of Neuroscience, April 11, 2007, 27(15):4052-4060; doi:10.1523/JNEUROSCI.3993-06.2007

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Neurobiology of Disease
Apolipoprotein Receptor 2 and X11/ß Mediate Apolipoprotein E-Induced Endocytosis of Amyloid-ß Precursor Protein and ß-Secretase, Leading to Amyloid-ß Production

Xiangyuan He,¹ Kathleen Cooley,^1,2 Charlotte H. Y. Chung,^1,3 Nassrin Dashti,⁴ and Jordan Tang^1,2,3

¹Protein Studies Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, ²Department of Biochemistry and Molecular Biology and ³Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, and ⁴Department of Medicine, Atherosclerosis Research Unit, University of Alabama at Birmingham Medical Center, Birmingham, Alabama 35294

Correspondence should be addressed to Dr. Jordan Tang, Protein Studies, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104. Email: jordan-tang{at}omrf.ouhsc.edu

The homeostasis of amyloid-ß (Aß) in the brain is critical to the pathogenesis of Alzheimer's disease (AD). Aß is a fragment of amyloid-ß precursor protein (APP) generated in neurons by two proteases, ß- and -secretases. APP and ß-secretase, both present on cell surface, are endocytosed into endosomes to produce Aß. The molecular mechanism by which neurons trigger the production of Aß 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, ß-secretase, and ApoER2 in neuroblastoma cells, leading to the production of Aß. This mechanism, mediated by adaptor protein X11 or X11ß (X11/ß), 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 Aß 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 Aß production, which may be important for the regulation of neuronal activity.

Key words: amyloid-ß precursor protein; apolipoprotein E; amyloid-ß; ß-secretase; endocytosis; Alzheimer's disease

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Received Sept. 13, 2006; revised Feb. 19, 2007; accepted Feb. 22, 2007.

Correspondence should be addressed to Dr. Jordan Tang, Protein Studies, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104. Email: jordan-tang{at}omrf.ouhsc.edu

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