Open AccessNGF controls APP cleavage by downregulating APP phosphorylation at Thr668: relevance for Alzheimer's disease
Author(s) -
Triaca Viviana,
Sposato Valentina,
Bolasco Giulia,
Ciotti Maria Teresa,
Pelicci Piergiuseppe,
Bruni Amalia C.,
Cupidi Chiara,
Maletta Raffaele,
Feligioni Marco,
Nisticò Robert,
Canu Nadia,
Calissano Pietro
Publication year - 2016
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12473
Subject(s) - tropomyosin receptor kinase a , basal forebrain , nerve growth factor , phosphorylation , amyloid precursor protein , microbiology and biotechnology , biology , kinase , low affinity nerve growth factor receptor , alzheimer's disease , neuroprotection , receptor , neuroscience , medicine , biochemistry , cholinergic , disease
Summary 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.