title: NGF controls APP cleavage by downregulating APP phosphorylation at Thr668: relevance for Alzheimer's disease.
abstract: NGF has been implicated in forebrain neuroprotection from amyloidogenesis and Alzheimer's disease (AD). However, the underlying molecular mechanisms are still poorly understood. Here, we investigated the role of NGF signalling in the metabolism of amyloid precursor protein (APP) in forebrain neurons using primary cultures of septal neurons and acute septo-hippocampal brain slices. In this study, we show that NGF controls the basal level of APP phosphorylation at Thr668 (T668) by downregulating the activity of the Ser/Thr kinase JNK(p54) through the Tyr kinase signalling adaptor SH2-containing sequence C (ShcC). We also found that the specific NGF receptor, Tyr kinase A (TrkA), which is known to bind to APP, fails to interact with the fraction of APP molecules phosphorylated at T668 (APP(pT668) ). Accordingly, the amount of TrkA bound to APP is significantly reduced in the hippocampus of ShcC KO mice and of patients with AD in which elevated APP(pT668) levels are detected. NGF promotes TrkA binding to APP and APP trafficking to the Golgi, where APP-BACE interaction is hindered, finally resulting in reduced generation of sAPPβ, CTFβ and amyloid-beta (1-42). These results demonstrate that NGF signalling directly controls basal APP phosphorylation, subcellular localization and BACE cleavage, and pave the way for novel approaches specifically targeting ShcC signalling and/or the APP-TrkA interaction in AD therapy.
authors.affiliation: Institute of Cell Biology and Neuroscience, National Research Council (CNR), Rome, Italy.|European Brain Research Institute (EBRI Foundation), Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Triaca
authors.affiliation: Institute of Cell Biology and Neuroscience, National Research Council (CNR), Rome, Italy.|European Brain Research Institute (EBRI Foundation), Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sposato
authors.affiliation: European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Bolasco
authors.affiliation: Institute of Cell Biology and Neuroscience, National Research Council (CNR), Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Ciotti
authors.affiliation: European Institute of Oncology (IFOM-IEO), Milan, Italy.
authors.forename: Piergiuseppe
authors.initials: P
authors.lastname: Pelicci
authors.affiliation: Regional Neurogenetic Center (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors.forename: Amalia C
authors.initials: AC
authors.lastname: Bruni
authors.affiliation: Regional Neurogenetic Center (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cupidi
authors.affiliation: Regional Neurogenetic Center (CRN), ASP Catanzaro, Lamezia Terme, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Maletta
authors.affiliation: European Brain Research Institute (EBRI Foundation), Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Feligioni
authors.affiliation: European Brain Research Institute (EBRI Foundation), Rome, Italy.
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
authors.affiliation: Institute of Cell Biology and Neuroscience, National Research Council (CNR), Rome, Italy.|Department of System Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Canu
authors.affiliation: European Brain Research Institute (EBRI Foundation), Rome, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Calissano
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D017353:Gene Deletion; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D010769:Phosphothreonine / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3 / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; C485682:Shc3 protein, mouse; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3; D010769:Phosphothreonine; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D048031:JNK Mitogen-Activated Protein Kinases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: AD; APP
  pT668; BACE; NGF; ShcC; TrkA-APP interaction