The Precursor Pro-Nerve Growth Factor Is the Predominant Form of Nerve Growth Factor in Brain and Is Increased in Alzheimer's Disease

Fahnestock, Margaret; Michalski, Bernadeta; Xu, Bin; Coughlin, Michael D.

doi:10.1006/mcne.2001.1016

Cited by 445 publications

(406 citation statements)

References 60 publications

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“…The high MW species have been shown to be predominant in non-neuronal tissues such as rat round spermatids (Chen et al 1997), human calf skin (Yiangou et al 2002), and neuronal tissues such as the dorsal root ganglion and spinal cord (Reinshagen et al 2000), the cortex and hippocampus (Fahnestock et al 2001), the SCG (Hasan et al 2003;Bierl et al 2005) and the trigeminal ganglion (Bierl and Isaacson 2005). Taken together, these findings suggest that high MW NGF species are abundant in the nervous system and may have their own biological activity.…”

Section: Function Of Ngf and Nt-3 Protein Speciesmentioning

confidence: 86%

“…While the male mouse submandibular gland is a rich source for mature 2.5S NGF (Mobley et al 1976;Lakshmanan et al 1989), most central and peripheral tissues appear to contain relatively small amounts of mature (13.5 or 16kDa) NGF protein (Fahnestock et al 2001;Bierl and Isaacson 2005) and higher MW NGF precursor species predominate. The high MW species have been shown to be predominant in non-neuronal tissues such as rat round spermatids (Chen et al 1997), human calf skin (Yiangou et al 2002), and neuronal tissues such as the dorsal root ganglion and spinal cord (Reinshagen et al 2000), the cortex and hippocampus (Fahnestock et al 2001), the SCG (Hasan et al 2003;Bierl et al 2005) and the trigeminal ganglion (Bierl and Isaacson 2005).…”

Section: Function Of Ngf and Nt-3 Protein Speciesmentioning

confidence: 99%

“…Indeed, subjects with Mild Cognitive Impairment (Peng et al, 2004) and Alzheimer's disease (Fahnestock et al 2001) have shown an increase in the 32kDa NGF precursor species in brain. Specific NGF species are altered in the development of early human diabetic neuropathy (Yiangou et al 2002) and tissues that show an age-related loss of sympathetic innervation also show a dramatic increase in the 25kDa proNGF-B precursor (Bierl and Isaacson 2005).…”

Section: Function Of Ngf and Nt-3 Protein Speciesmentioning

confidence: 99%

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Regulation of NGF and NT-3 protein expression in peripheral targets by sympathetic input

2007

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Nerve growth factor (NGF) and neurotrophin-3 (NT-3) are target-derived proteins that regulate innervating sympathetic neurons. Here, we used western blot analysis to investigate changes in NGF and NT-3 protein in several peripheral tissues following loss of sympathetic input. Following removal of the superior cervical ganglion (SCG), large molecular weight (MW) NGF species, including proNGF-A, were increased in distal intracranial SCG targets, such as pineal gland and extracerebral blood vessels (bv). Mature NGF was a minor species in these tissues and unchanged following sympathectomy. Large MW NGF species also were increased when sympathectomy was followed by in vivo NGF administration. Mature NT-3, which was abundant in controls, was significantly decreased in these targets following sympathetic denervation. The decrease in mature NT-3 was enhanced following NGF administration. The trigeminal ganglion, which provides sensory input to these targets, showed increased NGF, but decreased NT-3, in these treatments, demonstrating that decreased NT-3 at the targets did not result from enhanced NT-3 uptake. Unlike pineal gland and extracerebral bv, the external carotid artery, an extracranial proximal SCG target, showed no change in NGF following denervation, and mature NT-3 was significantly increased. Following NGF administration, NT-3 was significantly decreased. We provide evidence for sympathetic regulation of NGF and NT-3 in peripheral targets and that elevated NGF can depress NT-3. The differential response in distal and proximal adult targets is consistent with the idea that neurons innervating proximal and distal targets may serve different roles in regulating neurotrophin protein. In addition, we conclude that previous ELISA results showing increased NGF protein following sympathetic denervation may have resulted from increases in large MW species, rather than an increase in mature NGF.

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Section: Function Of Ngf and Nt-3 Protein Speciesmentioning

confidence: 86%

Section: Function Of Ngf and Nt-3 Protein Speciesmentioning

confidence: 99%

Section: Function Of Ngf and Nt-3 Protein Speciesmentioning

confidence: 99%

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Regulation of NGF and NT-3 protein expression in peripheral targets by sympathetic input

2007

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“…choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) with a decrease of cholinergic transmission (Svendsen et al, 1991;Venero et al, 1994). In contrast, the levels of proNGF, a precursor of NGF, which is the predominant form in human and rodent brain, are doubled in frontal and occipital cortex and in hippocampus in late-stage AD (Crutcher et al, 1993;Scott et al, 1995;Narisawa-Saito et al, 1996;Hellweg et al, 1998;Hock et al, 2000;Fahnestock et al, 2001;Peng et al, 2004) and appear to be 40%-50% increased in individuals with mild cognitive impairment (MCI) (Peng et al, 2004), suggesting that an unbalance in NGF processing may contribute, and in some instances cause, the onset of AD neurodegeneration. In this regard, an unbalance of the cascade of protease complex (plasminogen/plasmin; tPA,Neuroserpin, MMP-9) leading to a deficit of proNGF/NGF has been recently reported in human AD brains (Bruno et al, 2006;Cuello and Bruno, 2007).…”

Section: Ngf and Its Receptors In Admentioning

confidence: 99%

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

Calissano

Matrone

Amadoro

2010

Developmental Neurobiology

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Converging lines of evidence on the possible connection between NGF signaling and Alzheimer's diseases (AD) are unraveling new facets which could depict this neurotrophin (NTF) in a more central role. AD animal models have provided evidence that a shortage of NGF supply may induce an AD-like syndrome. In vitro experiments, moreover, are delineating a possible temporal and causal link between APP amiloydogenic processing and altered post-translational tau modifications. After NGF signaling interruption, the pivotal upstream players of the amyloid cascade (APP, b-secretase, and active form of c-secretase) are up-regulated, leading to an increased production of amyloid b peptide (Ab) and to its intracellular aggregation in molecular species of different sizes. Contextually, the Ab released pool generates an autocrine toxic loop in the same healthy neurons. At the same time tau protein undergoes anomalous, GSKb-mediated, phosphorylation at specific pathogenetic sites (Ser262 and Thr 231), caspase(s) and calpain-I-mediated truncation, detachment from microtubules with consequent cytoskeleton collapse and axonal transport impairment. All these events are inhibited when the amyloidogenic processing is reduced by b and c secretase inhibitors or anti-Ab antibodies and appear to be causally correlated to TrkA, p75CTF, Ab, and PS1 molecular association in an Ab-mediated fashion. In this scenario, the so-called trophic action exerted by NGF (and possibly also by other neurotrophins) in these targets neurons is actually the result of an anti-amyloidogenic activity. '

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“…Recently, evidence has been provided to support a model in which the formation of an inter-protomer disulfide bond in p75 allows a scissoring (or snail-tong) action upon NGF binding that promotes binding of intracellular adaptor proteins (Simi & Ibanez, 2010;Vilar et al, 2009). As mentioned above (Section 2.2), proneurotrophins may play significant role in AD, due to their ability to stimulate p75 in the absence of positive Trk signals thereby promoting apoptosis and death of neurons or glia (Cuello et al, 2010;Fahnestock et al, 2001;Teng, et al 2010). These effects are thought to be mediated by the same pathways ( Fig.…”

Section: P75 Signalingmentioning

confidence: 90%

Selectivity of Cell Signaling in the Neuronal Response Based on NGF Mutations and Peptidomimetics in the Treatment of Alzheimers Disease

Neet¹,

Mahapatra²,

Mehta³

2011

Alzheimer's Disease Pathogenesis-Core Concepts, Shifting Paradigms and Therapeutic Targets

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The Precursor Pro-Nerve Growth Factor Is the Predominant Form of Nerve Growth Factor in Brain and Is Increased in Alzheimer's Disease

Cited by 445 publications

References 60 publications

Regulation of NGF and NT-3 protein expression in peripheral targets by sympathetic input

Regulation of NGF and NT-3 protein expression in peripheral targets by sympathetic input

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

Selectivity of Cell Signaling in the Neuronal Response Based on NGF Mutations and Peptidomimetics in the Treatment of Alzheimers Disease

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