Enhancement of the nonamyloidogenic pathway by exogenous NGF in an Alzheimer transgenic mouse model

Yang, Chang Mo; Liu, Yuli; Ni, Xiuqin; Li, Ning; Zhang, Baohui; Xiu-bin, Fang

doi:10.1016/j.npep.2014.04.005

Cited by 33 publications

(18 citation statements)

References 41 publications

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“…Considering that NGF is important for cognitive functions, and it was found to have decreased with aging, this neurotrophic factor might contribute to an age-dependent decline in cognitive function [67][68][69]. Therefore, it plays a significant role in memory and cognition, and the development, survival and maintenance of cholinergic neurons [70], usually in the aging brain.…”

Section: Ngf and Agingmentioning

confidence: 99%

The involvement of BDNF, NGF and GDNF in aging and Alzheimer's disease

Budni¹,

Bellettini-Santos²,

Mina³

et al. 2015

Aging and disease

339

188

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Aging is a normal physiological process accompanied by cognitive decline. This aging process has been the primary risk factor for development of aging-related diseases such as Alzheimer's disease (AD). Cognitive deficit is related to alterations of neurotrophic factors level such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and glial cellderived neurotrophic factor (GDNF). These strong relationship between aging and AD is important to investigate the time which they overlap, as well as, the pathophysiological mechanism in each event. Considering that aging and AD are related to cognitive impairment, here we discuss the involving these neurotrophic factors in the aging process and AD.

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Section: Ngf and Agingmentioning

confidence: 99%

The involvement of BDNF, NGF and GDNF in aging and Alzheimer's disease

Budni¹,

Bellettini-Santos²,

Mina³

et al. 2015

Aging and disease

339

188

View full text Add to dashboard Cite

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“…In line with the modulatory role of NGF on amyloid precursor protein (APP) secretory pathway(s) in NGF-responsive cells (Rossner et al, 1998; Isacson et al, 2002; Matrone et al, 2008a,b; Calissano et al, 2010a,b), the ectopic administration of NGF stimulates the binding of its high-affinity receptor TrK kinase A (TrkA) to Amyloid Precursor Protein (APP) in in vitro cholinergic septal neurons favoring its subcellular localization in Golgi compartment—via downregulation in phosphorylation at the threonine 668 (T668)—which, in turn, reduces susceptibility to BACE cleavage and promotes the anti-amyloidogenic processing (Triaca et al, 2016). NGF supply via nasal route has been proved to in vivo modulate the secretase levels and, in turn, reduce the amyloid burden in APP/PS1 transgenic mice (Yang et al, 2014) and transgenic mice lacking the APP-TrkA interaction display forebrain damage and cognitive deficits (Matrone et al, 2012). Cholinergic neurons located in the nucleus basalis of Meynert of affected subjects exhibit a great sensibility to undergo neurofibrillary degeneration at early stages of AD neuropathology (Sassin et al, 2000; Mesulam et al, 2004), suggesting that NGF is also able to influence the tau metabolism, in addition to its effects on basal forebrain cholinergic function(s) and on APP processing (Schliebs and Arendt, 2006).…”

Section: Introductionmentioning

confidence: 99%

Impaired NGF/TrkA Signaling Causes Early AD-Linked Presynaptic Dysfunction in Cholinergic Primary Neurons

Latina

Caioli

Zona

et al. 2017

Front. Cell. Neurosci.

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Alterations in NGF/TrkA signaling have been suggested to underlie the selective degeneration of the cholinergic basal forebrain neurons occurring in vivo in AD (Counts and Mufson, 2005; Mufson et al., 2008; Niewiadomska et al., 2011) and significant reduction of cognitive decline along with an improvement of cholinergic hypofunction have been found in phase I clinical trial in humans affected from mild AD following therapeutic NGF gene therapy (Tuszynski et al., 2005, 2015). Here, we show that the chronic (10–12 D.I.V.) in vitro treatment with NGF (100 ng/ml) under conditions of low supplementation (0.2%) with the culturing serum-substitute B27 selectively enriches the basal forebrain cholinergic neurons (+36.36%) at the expense of other non-cholinergic, mainly GABAergic (−38.45%) and glutamatergic (−56.25%), populations. By taking advantage of this newly-developed septo-hippocampal neuronal cultures, our biochemical and electrophysiological investigations demonstrate that the early failure in excitatory neurotransmission following NGF withdrawal is paralleled by concomitant and progressive loss in selected presynaptic and vesicles trafficking proteins including synapsin I, SNAP-25 and α-synuclein. This rapid presynaptic dysfunction: (i) precedes the commitment to cell death and is reversible in a time-dependent manner, being suppressed by de novo external administration of NGF within 6 hr from its initial withdrawal; (ii) is specific because it is not accompanied by contextual changes in expression levels of non-synaptic proteins from other subcellular compartments; (ii) is not secondary to axonal degeneration because it is insensible to pharmacological treatment with known microtubule-stabilizing drug such paclitaxel; (iv) involves TrkA-dependent mechanisms because the effects of NGF reapplication are blocked by acute exposure to specific and cell-permeable inhibitor of its high-affinity receptor. Taken together, this study may have important clinical implications in the field of AD neurodegeneration because it: (i) provides new insights on the earliest molecular mechanisms underlying the loss of synaptic/trafficking proteins and, then, of synapes integrity which occurs in vulnerable basal forebrain population at preclinical stages of neuropathology; (ii) offers prime presynaptic-based molecular target to extend the therapeutic time-window of NGF action in the strategy of improving its neuroprotective in vivo intervention in affected patients.

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“…Furthermore, NGF treatment can ameliorate cognition and amyloidogenesis in AD transgenic models (Yang et al ., ), and AD clinical trials based on NGF gene therapy have produced promising results with respect to cognitive preservation (Rafii et al ., ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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SummaryNGF 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 (APPpT668). 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 APPpT668 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.

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Enhancement of the nonamyloidogenic pathway by exogenous NGF in an Alzheimer transgenic mouse model

Cited by 33 publications

References 41 publications

The involvement of BDNF, NGF and GDNF in aging and Alzheimer's disease

The involvement of BDNF, NGF and GDNF in aging and Alzheimer's disease

Impaired NGF/TrkA Signaling Causes Early AD-Linked Presynaptic Dysfunction in Cholinergic Primary Neurons

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

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