title: APP is phosphorylated by TrkA and regulates NGF/TrkA signaling.
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, Y(682), is indispensable for these essential functions of APP. It is therefore important to identify pathways that regulate phosphorylation of Y(682) as well as the role of Y(682) in vivo. TrkA is associated with both phosphorylation of APP-Y(682) 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 Y(682). Unpredictably, we also uncover that APP, and specifically Y(682), 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.
authors.affiliation: Institute of Cellular Biology and Neurobiology, National Council of Research of Rome, 00143 Rome, Italy. c.matrone@inmm.cnr.it
authors.forename: Carmela
authors.initials: C
authors.lastname: Matrone
authors.forename: Alessia P M
authors.initials: AP
authors.lastname: Barbagallo
authors.forename: Luca R
authors.initials: LR
authors.lastname: La Rosa
authors.forename: Fulvio
authors.initials: F
authors.lastname: Florenzano
authors.forename: Maria T
authors.initials: MT
authors.lastname: Ciotti
authors.forename: Delio
authors.initials: D
authors.lastname: Mercanti
authors.forename: Moses V
authors.initials: MV
authors.lastname: Chao
authors.forename: Pietro
authors.initials: P
authors.lastname: Calissano
authors.forename: Luciano
authors.initials: L
authors.lastname: D'Adamio
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation / Q000502:physiology; D020917:Receptor, trkA / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000502:physiology
chemical_list: D016564:Amyloid beta-Protein Precursor; D014443:Tyrosine; D020932:Nerve Growth Factor; D020917:Receptor, trkA