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

Abstract

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 (APPYG/YG mice). This mutation alters 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.

NGF controls APP cleavage by downregulating APP phosphorylation at Thr668: relevance for Alzheimer's disease

“…Previous studies have shown that transgenic mice lacking the APP–TrkA interaction demonstrate forebrain damage and cognitive deficits (Matrone et al ., ). Based on the effect of APP phosphorylation on APP–TrkA binding, the APP–TrkA interaction was investigated in the AD human brain where elevated APP pT668 levels have been reported (Lee et al ., ; Chang et al ., ).…”

The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes

“…Indeed, observations from the KI mice suggested that the primary function of APP resides in the sAPPα extracellular fragment, as described earlier and that much of the CTF, including the YENPTY domain, is dispensable. In this context, it is quite surprising that a mouse with a targeted APP Y682G knockin mutation, where the first tyrosine residue of the YENPTY motif was substituted by glycine, exhibited developmental defects in the absence of Aβ deposition and accumulation [11, 80]. This would not be predicted given the mild phenotypes seen in mice where the C-terminus of APP was deleted.…”

A new molecular explanation for age‐related neurodegeneration: The Tyr682 residue of amyloid precursor protein

“…Tyr682 and Tyr687 are the only APP residues that are phosphorylated in vitro . Tyr682 phosphorylation seems to be critical for APP signaling and activity because of its ability to profoundly regulate the APP interaction according to its phosphorylation state. Interestingly, the GY 682 ENPTY 687 motif is 100% conserved from C. elegans to humans (Fig.…”