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

Aging Cell

Carmela Matrone⁴  Siro Luvisetto³  Luca R. La Rosa³  Robert Tamayev¹  Annabella Pignataro³  Nadia Canu³  Li Yang²  Alessia P. M. Barbagallo¹  Fabrizio Biundo¹  Franco Lombino¹  Hui Zheng²  Martine Ammassari-Teule³ 

[1] Department of Microbiology and Immunology, Einstein College of Medicine, Bronx, NY, USA;Huffington Center on Aging and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;CNR - National Research Council, Cell Biology and Neurobiology Institute, Rome, Italy;Department of Medical Biochemistry, University of Aarhus, Aarhus C, Denmark

关键词: Alzheimer's disease;    amyloid precursor protein;    behavior;    cholinergic system;    dendritic spines;    TrkA receptor;    YENTPY domain;   

DOI  :  10.1111/acel.12009

来源: Wiley

【 摘 要 】

Summary

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 (APP^YG/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 APP^YG/YG mice. Here, we show that APP^YG/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 APP^YG/YG mice. The profound deficits caused by the Y⁶⁸² mutation underscore the biological importance of APP and indicate that APP^YG/YG are a valuable mouse model to study APP functions in physiological and pathological processes.

【 授权许可】

Unknown   
© 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland