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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.    Methodology/Principal Findings  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/Significance  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.

Tyr682 in the Intracellular Domain of APP Regulates Amyloidogenic APP Processing In Vivo