title: Tyr(682) in the intracellular domain of APP regulates amyloidogenic APP processing in vivo.
abstract: BACKGROUND
  The pathogenesis of Alzheimer's disease is attributed to misfolding of Amyloid-β (Aβ) peptides. Aβ is generated during amyloidogenic processing of Aβ-precursor protein (APP). Another characteristic of the AD brain is increased phosphorylation of APP amino acid Tyr(682). Tyr(682) is part of the Y(682)ENPTY(687) motif, a docking site for interaction with cytosolic proteins that regulate APP metabolism and signaling. For example, normal Aβ generation and secretion are dependent upon Tyr(682) in vitro. However, physiological functions of Tyr(682) are unknown.
  
  
  RESULTS
  To this end, we have generated an APP Y682G knock-in (KI) mouse to help dissect the role of APP Tyr(682) in 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 of amino acid Tyr(682) for the APP/Fe65 interaction in vivo.
  
  
  CONCLUSIONS
  Together, these observations point to an essential role of APP intracellular domain for normal APP processing and function in vivo, and provide rationale for further studies into physiological functions associated with this important phosphorylation site.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Alessia P M
authors.initials: AP
authors.lastname: Barbagallo
authors.forename: Richard
authors.initials: R
authors.lastname: Weldon
authors.forename: Robert
authors.initials: R
authors.lastname: Tamayev
authors.forename: Dawang
authors.initials: D
authors.lastname: Zhou
authors.forename: Luca
authors.initials: L
authors.lastname: Giliberto
authors.forename: Oded
authors.initials: O
authors.lastname: Foreman
authors.forename: Luciano
authors.initials: L
authors.lastname: D'Adamio
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D055879:Gene Knock-In Techniques; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013574:Synaptosomes / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D014443:Tyrosine