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
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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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