| Autor: |
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 |
| Předmět: |
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| Zdroj: |
Aging Cell; Dec2012, Vol. 11 Issue 6, p1084-1093, 10p, 4 Graphs |
| Abstrakt: |
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 682 YENPTY687 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 Trk A 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 Trk A 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 Trk A 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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