Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.654589
Title: ProBNDF and its receptors: pivotal mediators in Alzheimer's disease
Author: Kailainathan, Sumangali
ISNI:       0000 0004 5358 9963
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2014
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Abstract:
In neurons, brain derived neurotrophic factor (BDNF) facilitates cell survival, differentiation and long term potentiation (LTP) by binding predominantly to its receptor tyrosine kinase B (TrkB). In contrast, precursor BDNF (proBDNF) facilitates synaptic withdrawal, long term depression (LTD) and cell death via pan neurotrophin receptor (p75NTR) and sortilin. Additionally, a polymorphism in the pro region of proBDNF referred to as Val66Met, has been of interest in both healthy and diseased brain. The healthy Met66 carriers have been associated with reduced hippocampal volumes, episodic memory and protective for late-onset Alzheimer's disease (AD). AD is a progressive neurodegenerative disease characterised by synaptic withdrawal at early stages and with profound neuronal death at later stages. It was therefore hypothesised that proBDNF:mature BDNF ratio would be increased in AD brain, which may contribute to the detrimental effects seen in AD. It was also expected that the Val66Met polymorphic variants would bind differentially to their receptors and influence AD pathogenesis. Highly pure recombinant human (rh) proBDNF variants were successfully produced in this study. The rhproBDNF bound with three-fold less affinity to TrkB and p75NTR as shown by surface plasmon resonance and in rat phaeochromocytoma cells expressing TrkB (PC 12-TrkB) mediated three-fold less prosurvival signalling than rhBDNF. In cotiical neurons, rhproBDNF mediated dose dependent reduction in cotiical cell viability. Interestingly, Val66 variant facilitated hippocampal L TD whereas the Met66 variant blocked LTD. Apart from LTD, all binding and signalling profiles via TrkB, p75NTR and sortilin were independent of Val66Met polymorphism. This was indicative of a possible involvement of an additional coreceptor for p75NTR other than sortilin in LTD. Importantly in AD, even though BDNF and proBDNF levels were significantly reduced, the proBDNF:BDNF ratio was increased; independent of Val66Met polymorphism. Collectively, the increased proBDNF:BDNF ratio in AD patients would favour proBDNF-dependent neurotoxic signalling. However, compared to non-demented Val66 elderly, Met66 carriers had less proBDNF, suggesting a possible protective role for this polymorphism. Future studies using larger samples would further validate this finding
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.654589  DOI: Not available
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