A functional role for brain-derived neurotrophic factor from circulating blood platelets and potential neuroprotective applications

Want, Andrew 2022. A functional role for brain-derived neurotrophic factor from circulating blood platelets and potential neuroprotective applications. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Brain-derived neurotrophic factor (BDNF) is well known as a major effector of synaptic plasticity and for its role as a neuroprotectant. It has been extensively investigated as a possible treatment for neurodegenerative conditions such as glaucoma, a condition characterised by the progressive loss of retinal ganglion cells. Unfortunately, the physical properties of BDNF and a reduced effect over time due to interactions with its target receptor have prevented it from being translated into a clinical treatment. This thesis explores whether some of these challenges can be avoided by accessing an endogenous source of BDNF. In humans and other primates, blood platelets contain high concentrations of BDNF due to the expression of the BDNF gene in megakaryocytes. By contrast mice, typically used to investigate the impact of CNS lesions, have no demonstrable levels of BDNF in platelets and megakaryocytes. The potential contributions of platelet BDNF were explored in the context of glaucoma models, by comparing wild type mice to a novel, humanised mouse model engineered to express the Bdnf gene under the control of a megakaryocyte-specific promoter. A robust neuroprotective effect was seen on the retinal ganglion cells in both an ex vivo retinal explant and in vivo optic nerve crush models of retinal ganglion cell damage in the mice engineered to contain BDNF in platelets, demonstrated by preservation of dendrite complexity. Proof of concept experiments were then completed to try and enhance BDNF release from platelets to demonstrate how this concept could be translated into clinical practice. These findings shed light on how peripheral BDNF interacts with CNS structures. This not only suggests new strategies of BDNF delivery in neurodegenerative conditions, but indicates that platelet BDNF is likely to be a significant neuroprotective factor in primates.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Optometry and Vision Sciences
Subjects:	R Medicine > RE Ophthalmology
Uncontrolled Keywords:	BDNF, Retinal Ganglion Cells, Platelets, Glaucoma, Retina, Diolistics
Date of First Compliant Deposit:	30 January 2023
Last Modified:	10 Feb 2024 02:19
URI:	https://orca.cardiff.ac.uk/id/eprint/156307

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