title: Association of TrkA and APP Is Promoted by NGF and Reduced by Cell Death-Promoting Agents.
abstract: The amyloid precursor protein (APP) interacts with the tropomyosin receptor kinase A (TrkA) in normal rat, mouse, and human brain tissue but not in Alzheimer's disease (AD) brain tissue. However, it has not been reported whether the two proteins interact directly, and if so, which domains are involved. Clarifying these points will increase our understanding of the role and regulation of the TrkA/APP interaction in normal brain functioning as well as in AD. Here we addressed these questions using bimolecular fluorescence complementation (BiFC) and the proximity ligation assay (PLA). We demonstrated that exogenously expressed APP and TrkA associate through their juxtamembrane/transmembrane domains, to form a complex that localizes mainly to the plasma membrane, endoplasmic reticulum (ER) and Golgi. Formation of the complex was inhibited by p75NTR, ShcC and Mint-2. Importantly, we demonstrated that the association between endogenous APP and TrkA in primary septal neurons were modified by NGF, or by drugs that either inhibit ER-to-Golgi transport or perturb microtubules and microfilaments. Interestingly, several agents that induce cell death [amyloid β (Aβ)-peptide, staurosporine and rapamycin], albeit via different mechanisms, all caused dissociation of APP/TrkA complexes and increased production of C-terminal fragment (β-CTF) APP fragment. These findings open new perspectives for investigating the interplay between these proteins during neurodegeneration and AD.
authors.affiliation: Department of System Medicine, University of Rome "Tor Vergata"Rome, Italy; Institute of Cellular Biology and Neurobiology, National Council of Research of RomeRome, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Canu
authors.affiliation: Institute of Cellular Biology and Neurobiology, National Council of Research of Rome Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Pagano
authors.affiliation: Institute of Cellular Biology and Neurobiology, National Council of Research of Rome Rome, Italy.
authors.forename: Luca Rosario
authors.initials: LR
authors.lastname: La Rosa
authors.affiliation: Institute of Cellular Biology and Neurobiology, National Council of Research of Rome Rome, Italy.
authors.forename: Marsha
authors.initials: M
authors.lastname: Pellegrino
authors.affiliation: Institute of Cellular Biology and Neurobiology, National Council of Research of Rome Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Ciotti
authors.affiliation: Institute of Cellular Biology and Neurobiology, National Council of Research of Rome Rome, Italy.
authors.forename: Delio
authors.initials: D
authors.lastname: Mercanti
authors.affiliation: Institute of Cellular Biology and Neurobiology, National Council of Research of Rome Rome, Italy.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Moretti
authors.affiliation: Institute of Cellular Biology and Neurobiology, National Council of Research of RomeRome, Italy; European Brain Research InstituteRome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sposato
authors.affiliation: Institute of Cellular Biology and Neurobiology, National Council of Research of RomeRome, Italy; European Brain Research InstituteRome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Triaca
authors.affiliation: Institute of Cellular Biology and Neurobiology, National Council of Research of Rome Rome, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Petrella
authors.affiliation: Information Processing Biology Unit, Okinawa Institute of Science and Technology Graduate University Okinawa, Japan.
authors.forename: Ichiro N
authors.initials: IN
authors.lastname: Maruyama
authors.affiliation: Institute of Cellular Biology and Neurobiology, National Council of Research of Rome Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Levi
authors.affiliation: European Brain Research InstituteRome, Italy; Institute of Cellular Biology and Neurobiology, National Council of Research of RomeRome, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Calissano
keywords: APP; Alzheimer’s disease; BiFC; CBFN; NGF; TrkA; proximity ligation assay