Tyr682 in the Aβ-precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance

Carmela Matrone, Siro Luvisetto, Luca R. La Rosa, Robert Tamayev, Annabella Pignataro, Nadia Canu, Li Yang, Alessia P.M. Barbagallo, Fabrizio Biundo, Franco Lombino, Hui Zheng, Martine Ammassari-Teule, Luciano D'Adamio

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Processing of Aβ-precursor protein (APP) plays an important role in Alzheimer's disease (AD) pathogenesis. The APP intracellular domain contains residues important in regulating APP function and processing, in particular the 682YENPTY687 motif. To dissect the functions of this sequence in vivo, we created an APP knock-in allele mutating Y682 to Gly (APPYG/YG mice). This mutation alters the processing of APP and TrkA signaling and leads to postnatal lethality and neuromuscular synapse defects when expressed on an APP-like protein 2 KO background. This evidence prompted us to characterize further the APPYG/YG mice. Here, we show that APPYG/YG mice develop aging-dependent decline in cognitive and neuromuscular functions, a progressive reduction in dendritic spines, cholinergic tone, and TrkA levels in brain regions governing cognitive and motor functions. These data are consistent with our previous findings linking NGF and APP signaling and suggest a causal relationship between altered synaptic connectivity, cholinergic tone depression and TrkA signaling deficit, and cognitive and neuromuscular decline in APPYG/YG mice. The profound deficits caused by the Y682 mutation underscore the biological importance of APP and indicate that APPYG/YG are a valuable mouse model to study APP functions in physiological and pathological processes.

Original languageEnglish (US)
Pages (from-to)1084-1093
Number of pages10
JournalAging cell
Volume11
Issue number6
DOIs
StatePublished - Dec 1 2012

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • Behavior
  • Cholinergic system
  • Dendritic spines
  • TrkA receptor
  • YENTPY domain

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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    Matrone, C., Luvisetto, S., La Rosa, L. R., Tamayev, R., Pignataro, A., Canu, N., Yang, L., Barbagallo, A. P. M., Biundo, F., Lombino, F., Zheng, H., Ammassari-Teule, M., & D'Adamio, L. (2012). Tyr682 in the Aβ-precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance. Aging cell, 11(6), 1084-1093. https://doi.org/10.1111/acel.12009