The Biology of Neurotrophins, Signalling Pathways, and Functional Peptide Mimetics of Neurotrophins and their Receptors
The neurotrophins are a family of closely related proteins that were first identified as survival factors for sympathetic and sensory neurons, and have since been shown to control a number of aspects of survival, development and function of neurons in both the central and peripheral nervous systems. Limiting quantities of neurotrophins during development control the numbers of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. Biological effects of each of the four mammalian neurotrophins are mediated through activation of one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC). In addition, all neurotrophins activate the p75 neurotrophin receptor (p75(NTR)), a member of the tumour necrosis factor receptor superfamily. Nerve growth factor (NGF), the best characterised member of the neurotrophin family, sends its survival signals through activation of TrkA and can induce death by binding to p75(NTR). Neurotrophin engagement of Trk receptors leads to activation of Ras, phosphatidylinositol 3-kinase, phospholipase C-gamma1 and signalling pathways controlled through these proteins, including the mitogen-activated protein kinases. Neurotrophin availability is required into adulthood, where they control synaptic function and plasticity, and sustain neuronal cell survival, morphology and differentiation. Preclinical studies point to the therapeutic potential of neurotrophic factors in preventing or slowing the progression of neurodegenerative conditions. Given the difficulties inherent with a protein therapeutic approach to treating central nervous system disorders, increasing attention has turned to the development of alternative strategies and, in particular, small molecule mimetics. This article will provide an overview of neurotrophin biology, their receptors, and signalling pathways, followed by a description of functional mimetics of neurotrophins acting at Trk receptors. Moreover, exciting recent data describing G-protein-coupled receptor transactivation of Trk receptors and their downstream signalling pathways raise the possibility of using small molecules to elicit neuroprotective effects.
Available from: Sighild Lemarchant
- "The neurotrophic factor production after ADAMTS-4 treatment has not been studied in SCI studies so far, but we could hypothesize that even if ADAMTS-4 also induced a decrease of neurotrophic factor production in the context of SCI, its impact may be negligible compared to the great benefit of the CSPGs/PNNs degradation-induced neuroregeneration[5,6]. Among the neurotrophic factors modulated by ADAMTS-4, NGF is of particular interest as it exerts dual roles on neuronal survival/cell death depending on whether it activates the tyrosine kinase receptor TrkA or the tumor, two receptors induced after injury and in ALS[43,44]. Although astrocyte-derived NGF was described to promote motoneuron cell death through the activation of p75 NTR receptor during ALS[45,46], it was also described that the surviving motoneurons expressed the TrkA receptor, suggesting that NGF-TrkA signaling also plays a critical role in the survival of motoneurons. "
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ABSTRACT: A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) proteoglycanases are specialized in the degradation of chondroitin sulfate proteoglycans and participate in mechanisms mediating neuroplasticity. Despite the beneficial effect of ADAMTS-4 on neurorepair after spinal cord injury, the functions of ADAMTS proteoglycanases in other CNS disease states have not been studied. Therefore, we investigated the expression, effects and associated mechanisms of ADAMTS-4 during amyotrophic lateral sclerosis (ALS) in the SOD1 G93A mouse model.
ADAMTS-4 expression and activity were reduced in the spinal cord of SOD1 G93A mice at disease end-stage when compared to WT littermates. To counteract the loss of ADAMTS-4, SOD1 G93A and WT mice were treated with saline or a recombinant ADAMTS-4 before symptom onset. Administration of ADAMTS-4 worsened the prognosis of SOD1 G93A mice by accelerating clinical signs of neuromuscular dysfunctions. The worsened prognosis of ADAMTS-4-treated SOD1 G93A mice was accompanied by increased degradation of perineuronal nets enwrapping motoneurons and increased motoneuron degeneration in the lumbar spinal cord. Motoneurons of ADAMTS-4-treated SOD1 G93A mice were more vulnerable to degeneration most likely due to the loss of their extracellular matrix envelopes. The decrease of neurotrophic factor production induced by ADAMTS-4 in vitro and in vivo may also contribute to a hostile environment for motoneuron especially when devoid of a net.
This study suggests that the reduction of ADAMTS-4 activity during the progression of ALS pathology may be an adaptive change to mitigate its neurodegenerative impact in CNS tissues. Therapies compensating the compromized ADAMTS-4 activity are likely not promising approaches for treating ALS.
Available from: Andrey D Ivanov
- "It has been shown that neurotrophins, especially NGF and BDNF, can have a neuroprotective effect in AD-like conditions (Wang et al., 2002; Skaper, 2008; Bruno et al., 2009). NGF injection prevents degeneration of cholinergic neurons after fornix lesion or administration of toxins (Williams et al., 1986; Koliatsos et al., 1990; Charles et al., 1996; Blesch et al., 2005; Skaper, 2008). Successful experiments on NGF-producing fibroblasts transplantation into the affected brain structures were reported (Rosenberg et al., 1988; Chen and Gage, 1995; Tuszynski et al., 1996). "
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ABSTRACT: We have explored the potential neuroprotective effect of local lentiviraly-mediated overexpression of nerve growth factor (NGF) on in vivo long-term potentiation (LTP) in the rat hippocampus under pathological conditions. The suspension of lentiviral particles was prepared using a genetic construct containing the human NGF gene under the control of a neuron-specific CaMKII promoter. Two weeks after the viral injection NGF concentration in the hippocampus doubled. In vivo recordings of total electrical activity in the dentate gyrus were performed. While the increased expression of NGF did not affect the amplitude of evoked postsynaptic potentials recorded after a high-frequency stimulation of the perforant path, it prevented the LTP decline induced by the i.c.v. administration of 50nM beta-amyloid (25-35) 1h prior to tetanization. Our results demonstrate that increased endogenous NGF concentration can rescue hippocampal neuronal function from beta-amyloid peptide induced impairment.
Copyright © 2015. Published by Elsevier B.V.
Available from: Stephen D Ginsberg
- "neurotrophin receptor expression levels are downregulated , and neurotrophin expression appears to partially parallel these decreases, possible interventions include gene therapy (Tuszynski 2002, 2007; Maeder et al., 2013), modifications in target-derived neurotrophic support (Cooper et al., 2001; Howe and Mobley, 2004; Salehi et al., 2006) and, potentially, receptor transactivation (Rajagopal et al., 2004; Skaper, 2008; Huang and McNamara, 2012) to increase TrkA, TrkB, and/or TrkC signaling for pro-survival effects. Importantly, increasing neurotrophic support can be used in conjunction with so-called monotherapies that aim to modify amyloid and/or tau levels in AD and DS (D'Alton and George, 2011; Lane et al., 2012) for a more sophisticated treatment regimen with a higher likelihood of success by affecting multiple targets during the presumed prodromal and neurodegenerative phases of DS and AD. "
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ABSTRACT: Down syndrome (DS) is the most prevalent cause of intellectual disability (ID). Individuals with DS show a variety of cognitive deficits, most notably in hippocampal learning and memory, and display pathological hallmarks of Alzheimer’s disease (AD), with neurodegeneration of cholinergic basal forebrain (CBF) neurons. Elucidation of the molecular and cellular underpinnings of neuropathology has been assessed via gene expression analysis in a relevant animal model, termed the Ts65Dn mouse. The Ts65Dn mouse is a segmental trisomy model of DS which mimics DS/AD pathology, notably age-related cognitive dysfunction and degeneration of basal forebrain cholinergic neurons (BFCNs). To determine expression level changes, molecular fingerprinting of Cornu Ammonis 1 (CA1) pyramidal neurons was performed in adult (4-9 month old) Ts65Dn mice, at the initiation of BFCN degeneration. To quantitate transcriptomic changes during this early time period, laser capture microdissection (LCM), terminal continuation (TC) RNA amplification, custom-designed microarray analysis, and subsequent validation of individual transcripts by qPCR and protein analysis via immunoblotting was performed. Results indicate significant alterations within CA1 pyramidal neurons of Ts65Dn mice compared to normal disomic (2N) littermates, notably in the downregulation of neurotrophins and their cognate neurotrophin receptors among other classes of transcripts relevant to neurodegeneration. These results of this single population gene expression analysis at the time of septohippocampal deficits in a trisomic mouse model shed light on a vulnerable circuit that may cause the AD-like pathology invariably seen in DS that could help to identify mechanisms of degeneration, and provide novel gene targets for therapeutic interventions. J. Comp. Neurol., 2014. © 2014 Wiley Periodicals, Inc.
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