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 language | English |
|---|---|
| Pages (from-to) | 1084-1093 |
| Number of pages | 10 |
| Journal | Aging Cell |
| Volume | 11 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Dec 2012 |
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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
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 journal › Article
}
TY - JOUR
T1 - Tyr682 in the Aβ-precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance
AU - Matrone, Carmela
AU - Luvisetto, Siro
AU - La Rosa, Luca R.
AU - Tamayev, Robert
AU - Pignataro, Annabella
AU - Canu, Nadia
AU - Yang, Li
AU - Barbagallo, Alessia P M
AU - Biundo, Fabrizio
AU - Lombino, Franco
AU - Zheng, Hui
AU - Ammassari-Teule, Martine
AU - D'Adamio, Luciano
PY - 2012/12
Y1 - 2012/12
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Amyloid precursor protein
KW - Behavior
KW - Cholinergic system
KW - Dendritic spines
KW - TrkA receptor
KW - YENTPY domain
UR - http://www.scopus.com/inward/record.url?scp=84869164516&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84869164516&partnerID=8YFLogxK
U2 - 10.1111/acel.12009
DO - 10.1111/acel.12009
M3 - Article
VL - 11
SP - 1084
EP - 1093
JO - Aging Cell
JF - Aging Cell
SN - 1474-9718
IS - 6
ER -