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

22 Citations (Scopus)

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
Pages (from-to)1084-1093
Number of pages10
JournalAging Cell
Volume11
Issue number6
DOIs
Publication statusPublished - Dec 2012

Fingerprint

Protein Precursors
Cognition
Cholinergic Agents
Physiological Phenomena
Dendritic Spines
Mutation
Protein Domains
Nerve Growth Factor
Pathologic Processes
Synapses
Alzheimer Disease
Alleles
Depression
Brain

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Ageing

Cite this

Matrone, C., Luvisetto, S., La Rosa, L. R., Tamayev, R., Pignataro, A., Canu, N., ... 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

Tyr682 in the Aβ-precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance. / Matrone, Carmela; Luvisetto, Siro; La Rosa, Luca R.; Tamayev, Robert; Pignataro, Annabella; Canu, Nadia; Yang, Li; Barbagallo, Alessia P M; Biundo, Fabrizio; Lombino, Franco; Zheng, Hui; Ammassari-Teule, Martine; D'Adamio, Luciano.

In: Aging Cell, Vol. 11, No. 6, 12.2012, p. 1084-1093.

Research output: Contribution to journalArticle

Matrone, C, Luvisetto, S, La Rosa, LR, Tamayev, R, Pignataro, A, Canu, N, Yang, L, Barbagallo, APM, 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, vol. 11, no. 6, pp. 1084-1093. https://doi.org/10.1111/acel.12009
Matrone, Carmela ; Luvisetto, Siro ; La Rosa, Luca R. ; Tamayev, Robert ; Pignataro, Annabella ; Canu, Nadia ; Yang, Li ; Barbagallo, Alessia P M ; Biundo, Fabrizio ; Lombino, Franco ; Zheng, Hui ; Ammassari-Teule, Martine ; D'Adamio, Luciano. / Tyr682 in the Aβ-precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance. In: Aging Cell. 2012 ; Vol. 11, No. 6. pp. 1084-1093.
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