APP is Phosphorylated by TrkA and regulates NGF/TrkA signaling

Carmela Matrone, Alessia P.M. Barbagallo, Luca R. La Rosa, Fulvio Florenzano, Maria T. Ciotti, Delio Mercanti, Moses V. Chao, Pietro Calissano, Luciano D'Adamio

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

The pathogenic model of Alzheimer's disease (AD) posits that aggregates of amyloid β, a product of amyloid precursor protein (APP) processing, cause dementia. However, alterations of normal APP functions could contribute to AD pathogenesis, and it is therefore important to understand the role of APP. APP is a member of a gene family that shows functional redundancy as documented by the evidence that single knock-out mice are viable, whereas mice with combined deletions of APP family genes die shortly after birth. A residue in the APP intracellular region, Y682, is indispensable for these essential functions of APP. It is therefore important to identify pathways that regulate phosphorylation of Y682 as well as the role of Y682 in vivo. TrkA is associated with both phosphorylation of APP-Y682 and alteration of APP processing, suggesting that tyrosine phosphorylation of APP links APP processing and neurotrophic signaling to intracellular pathways associated with cellular differentiation and survival. Here we have tested whether the NGF/TrkA signaling pathway is a physiological regulator of APP phosphorylation. We find that NGF induces tyrosine phosphorylation of APP, and that APP interacts with TrkA and this interaction requires Y682. Unpredictably, we also uncover that APP, and specifically Y682, regulates activation of the NGF/TrkA signaling pathway in vivo, the subcellular distribution of TrkA and the sensitivity of neurons to the trophic action of NGF. This evidence suggests that these two membrane protein's functions are strictly interconnected and that the NGF/TrkA signaling pathway is involved in AD pathogenesis and can be used as a therapeutic target.

Original languageEnglish (US)
Pages (from-to)11756-11761
Number of pages6
JournalJournal of Neuroscience
Volume31
Issue number33
DOIs
StatePublished - Aug 17 2011

ASJC Scopus subject areas

  • Neuroscience(all)

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