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

Aging cell (2016-04-15)
Viviana Triaca, Valentina Sposato, Giulia Bolasco, Maria Teresa Ciotti, Piergiuseppe Pelicci, Amalia C Bruni, Chiara Cupidi, Raffaele Maletta, Marco Feligioni, Robert Nisticò, Nadia Canu, Pietro Calissano
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-APP A4 Antibody, a.a. 66-81 of APP {NT}, clone 22C11, clone 22C11, Chemicon®, from mouse
Sigma-Aldrich
Anti-BACE Antibody, CT, clone 61-3E7, clone 61-3E7, Chemicon®, from mouse
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Anti-Amyloid Precursor Protein, C-Terminal antibody produced in rabbit, IgG fraction of antiserum, buffered aqueous solution
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Anti-p35 (Cdk5 Regulator) antibody produced in rabbit, IgG fraction of antiserum, buffered aqueous solution
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Anti-β-Actin−Peroxidase antibody, Mouse monoclonal, clone AC-15, purified from hybridoma cell culture
Sigma-Aldrich
Anti-phospho-APP (pThr668) antibody produced in rabbit, affinity isolated antibody, aqueous glycerol solution, 10 blots
Sigma-Aldrich
Anti-Choline Acetyltransferase Antibody, Chemicon®, from goat