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tyr682 in the intracellular domain of app regulates amyloidogenic app processing in vivotyr682胞内域的应用调节amyloidogenic应用处理体内.pdf

发布:2017-09-11约8.8万字共11页下载文档
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Tyr682 in the Intracellular Domain of APP Regulates Amyloidogenic APP Processing In Vivo 1. 1. 1. 1 3 Alessia P. M. Barbagallo , Richard Weldon , Robert Tamayev , Dawang Zhou , Luca Giliberto , Oded 2 1 Foreman , Luciano D’Adamio * 1 Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America, 2 Department of Laboratory Animal Health, The Jackson Laboratory, Bar Harbor, Maine, United States of America, 3 The Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institute for Medical Research, North Shore – LIJ, Manhasset, New York, United States of America Abstract Background: The pathogenesis of Alzheimer’s disease is attributed to misfolding of Amyloid- b (Ab) peptides. Ab is generated during amyloidogenic processing of Ab-precursor protein (APP). Another characteristic of the AD brain is increased phosphorylation of APP amino acid Tyr682. Tyr682 is part of the Y682ENPTY687 motif, a docking site for interaction with cytosolic proteins that regulate APP metabolism and signaling. For example, normal Ab generation and secretion are dependent upon Tyr682 in vitro. However, physiological functions of Tyr682 are unknown. Methodology/Principal Findings: To this end, we have generated an APP Y682G knock-in (KI) mouse to help dissect the role of APP Tyr682in vivo. We have analyzed proteolytic products from both the amyloidogenic and non-amyloidogenic processing of APP and measure a profound shift towards non-amyloidogenic processing in APP KI mice. In addition, we demonstrate the essential nature o
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