title: Tyr682 in the Aβ-precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance.
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 (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.
authors.affiliation: CNR--National Research Council, Cell Biology and Neurobiology Institute, Rome, 00143, Italy. matrone@biokemi.au.dk
authors.forename: Carmela
authors.initials: C
authors.lastname: Matrone
authors.forename: Siro
authors.initials: S
authors.lastname: Luvisetto
authors.forename: Luca R
authors.initials: LR
authors.lastname: La Rosa
authors.forename: Robert
authors.initials: R
authors.lastname: Tamayev
authors.forename: Annabella
authors.initials: A
authors.lastname: Pignataro
authors.forename: Nadia
authors.initials: N
authors.lastname: Canu
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Alessia P M
authors.initials: AP
authors.lastname: Barbagallo
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Biundo
authors.forename: Franco
authors.initials: F
authors.lastname: Lombino
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Martine
authors.initials: M
authors.lastname: Ammassari-Teule
authors.forename: Luciano
authors.initials: L
authors.lastname: D'Adamio
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003071:Cognition; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D009045:Motor Endplate / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D014443:Tyrosine; D020917:Receptor, trkA; D005998:Glycine