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The Journal of Neuroscience, June 10, 2009, 29(23):7459-7473; doi:10.1523/JNEUROSCI.4872-08.2009

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Neurobiology of Disease
Interaction of Reelin with Amyloid Precursor Protein Promotes Neurite Outgrowth

Hyang-Sook Hoe,^1 * Kea Joo Lee,^2 * Rosalind S. E. Carney,³ Jiyeon Lee,⁴ Alexandra Markova,⁵ Ji-Yun Lee,² Brian W. Howell,⁶ Bradley T. Hyman,⁵ Daniel T. S. Pak,² Guojun Bu,⁴ and G. William Rebeck¹

Departments of ¹Neuroscience and ²Pharmacology, Georgetown University Medical Center, Washington, DC 20057-1464, ³Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010-2970, ⁴Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, ⁵Department of Neurology, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disorders, Charlestown, Massachusetts 02129, and ⁶Neurogenetics Branch, National Institute of Neurological Disorders and Stroke Porter Neuroscience Research Center, National Institutes of Health, Bethesda, Maryland 20892-3705

Correspondence should be addressed to G. William Rebeck, Georgetown University, 3970 Reservoir Road Northwest, Washington, DC 20057-1464. Email: gwr2{at}georgetown.edu

The processing of amyloid precursor protein (APP) to Aβ is an important event in the pathogenesis of Alzheimer's disease, but the physiological function of APP is not well understood. Our previous work has shown that APP processing and Aβ production are regulated by the extracellular matrix protein Reelin. In the present study, we examined whether Reelin interacts with APP, and the functional consequences of that interaction in vitro. Using coimmunoprecipitation, we found that Reelin interacted with APP through the central domain of Reelin (repeats 3–6) and the E1 extracellular domain of APP. Reelin increased cell surface levels of APP and decreased endocytosis of APP in hippocampal neurons in vitro. In vivo, Reelin levels were increased in brains of APP knock-out mice and decreased in APP-overexpressing mice. RNA interference knockdown of APP decreased neurite outgrowth in vitro and prevented Reelin from increasing neurite outgrowth. Knock-out of APP or Reelin decreased dendritic arborization in cortical neurons in vivo, and APP overexpression increased dendritic arborization. APP and Reelin have previously been shown to promote neurite outgrowth through interactions with integrins. We confirmed that APP interacted with 3β1 integrin, and 3β1 integrin altered APP trafficking and processing. Addition of an 3β1 integrin antibody prevented APP and Reelin-induced neurite outgrowth. These findings demonstrate that Reelin interacts with APP, potentially having important effects on neurite development.

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Received Oct. 9, 2008; revised March 19, 2009; accepted April 15, 2009.

Correspondence should be addressed to G. William Rebeck, Georgetown University, 3970 Reservoir Road Northwest, Washington, DC 20057-1464. Email: gwr2{at}georgetown.edu

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