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Background  Processing of Aβ-precursor protein (APP) plays an important role in Alzheimer's Disease (AD) pathogenesis. Thr residue at amino acid 668 of the APP intracellular domain (AID) is highly conserved. When phosphorylated, this residue generates a binding site for Pin1. The interaction of APP with Pin1 has been involved in AD pathogenesis.    Methodology/Principal Findings  To dissect the functions of this sequence  in vivo , we created an  APP  knock-in allele, in which Thr 668  is replaced by an Ala (T 668 A). Doubly deficient  APP / APP-like protein 2  ( APLP2 ) mice present postnatal lethality and neuromuscular synapse defects. Previous work has shown that the APP intracellular domain is necessary for preventing early lethality and neuromuscular junctions (NMJ) defects. Crossing the T 668 A allele into the  APLP2  knockout background showed that mutation of Thr 668  does not cause a defective phenotype. Notably, the T 668 A mutant APP is able to bind Mint1.    Conclusions/Significance  Our results argue against an important role of the Thr 668  residue in the essential function of APP in developmental regulation. Furthermore, they indicate that phosphorylation at this residue is not functionally involved in those APP-mediated functions that prevent (NMJ) defects and early lethality in  APLP2  null mice.

The Intracellular Threonine of Amyloid Precursor Protein That Is Essential for Docking of Pin1 Is Dispensable for Developmental Function