The Biology of Neurotrophins, Signalling Pathways, and Functional Peptide Mimetics of Neurotrophins and their Receptors

Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline Research & Development Limited, New Frontiers Science Park, Third Avenue, CM19 5AW, Harlow, Essex, UK.
CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) (Impact Factor: 2.63). 03/2008; 7(1):46-62. DOI: 10.2174/187152708783885174
Source: PubMed


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.

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    • "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.
    Brain research 08/2015; DOI:10.1016/j.brainres.2015.07.051 · 2.84 Impact Factor
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    • "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.
    The Journal of Comparative Neurology 01/2015; 523(1). DOI:10.1002/cne.23663 · 3.23 Impact Factor
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    • "The second is the tyrosine kinase receptor TrkB. Pro-BDNF binds preferentially to p75NTR to mediate apoptosis and mature BDNF preferentially binds to TrkB to promote survival (for a review, see Skaper, 2008). "
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    ABSTRACT: BDNF (Brain Derived Neurotrophic Factor) is a member of the neurotrophin family, and it is implicated in regulating brain development and function. The BDNF gene organization and coding sequence are conserved in all vertebrates.. The present survey was conducted in a teleost fish, Nothobranchius furzeri, because it is an emerging model of ageing studies due to its short lifespan and shows the high rate of adult neurogenesis typical of anamniotes. The present survey reports: a) the identification and characterization of the cDNA fragment encoding BDNF protein; b) the localization of BDNF in the whole brain. BDNF mRNA expression was assessed by in situ hybridization, by employing antisense RNA probe; BDNF protein was detected by employing a sensitive immunohistochemical technique, along with highly specific affinity-purified antibodies to BDNF. Both BDNF mRNA and protein were detected in neurons and glial cells of all regions of the brain of N. furzeri. Interestingly, BDNF was localized also in brain areas involved in adult neurogenic activities, suggesting a specific role for this neurotrophic factor in controlling cell proliferation. These results provide baseline information for future studies concerning BDNF involvement in ageing processes of the teleost brain. J. Comp. Neurol., 2013. © 2013 Wiley Periodicals, Inc.
    The Journal of Comparative Neurology 04/2014; 522(5). DOI:10.1002/cne.23457 · 3.23 Impact Factor
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