GW4 BioMed MRC DTP PhD Studentship: Polyphenols as inhibitors of tau toxicity: protecting neuronal network function in Alzheimer’s Disease

This project is one of a number that are in competition for funding from the ‘GW4 BioMed MRC Doctoral Training Partnership’ which is offering up to 19 studentships for entry in September/October 2018. The DTP brings together the Universities of Bath, Bristol, Cardiff and Exeter to develop the next generation of biomedical researchers.

Supervisory team for this project:
Dr Robert Williams (Bath), Dr Jon Brown (Exeter) and Dr Jody Mason (Bath).

Project description:

There is an urgent need for new therapeutic approaches to treat Alzheimer’s Disease. This interdisciplinary project will use newly developed biochemical screening approaches, state-of the art cell imaging in neurons and in vivo neurophysiology in transgenic mice to determine if novel polyphenolics inhibit tau-induced synaptic dysfunction in AD.

The emergence of tau pathology is a key driver of Alzheimer’s Disease (AD), making tau an attractive target for the development of new therapeutics for AD. Tau is a natively unfolded, soluble, microtubule-associated protein showing little tendency for aggregation, however, in AD misfolded tau leads to the formation of toxic oligomeric species which trigger neuronal dysfunction and seed self-propagation. A number of polyphenols disrupt tau aggregation in vitro but typically have poor bioavailability, membrane penetrance, and low potency.

Notably, we recently showed that oral administration of the polyphenol (2R,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (EC) to rTg4510 tau transgenic mice halted the appearance of high molecular weight tau species within the brain. This critical proof of principle observation suggests that orally delivered polyphenols targeted to tau could potentially provide benefit in AD but we do not yet know if this reduction in tau pathology blocks neurotoxicity or reverses deficits in synaptic function. Our aim is to determine if EC, or structural analogues with improved efficacy; confer protection against tau toxicity, inhibit propagation of tau and reverse deficits in neuronal network dysfunction.

Using EC as a prototypical lead compound we will;

1. Screen a library of structurally related polyphenolics, including +/- stereoisomers and key metabolites, for the ability to inhibit tau aggregation inside cells. This will utilise a novel split reporter enzyme approach which relies on the ability of the polyphenols to cross the cell-membrane, bind to tau and inhibit associated toxicity in order to enable cell survival. The assay will exploit the recently identified 31-residue minimal peptide sequence and active conformational nucleus of tau that defines the self-propagating aggregation of the microtubule binding region.

2. Test positive hits (from 1) for their ability to inhibit tau toxicity and tau propagation in primary neurons. Toxicity will be induced by exposure of neurons to recombinant oligomeric tau and viability assessed by live cell imaging coupled to high content microscopy. Tau propagation will be monitored by assessing the transfer of fluorescently tagged tau from transfected to untransfected neighbouring neurons in microfluidic chambers. Experiments will incorporate full concentration, kinetic and cell penetrance measurements.

3. Take a lead polyphenolic (from 1, 2) to test against alterations in synaptic circuitry in rTg4510 mice. This will focus on our recently published data showing deficits in gamma frequency oscillations within the medial entorhinal cortex which could underlie aberrant spatial memory and orientation in AD.

Collectively the study will provide new mechanistic insight into the link between tau and synaptic dysfunction and will signpost future rationale drug discovery aimed at disrupting tau toxicity to halt progression and provide symptomatic benefit in AD.


IMPORTANT: In order to apply for this project, you should apply using the DTP’s online application form. More information on the application process may be found here: http://www.gw4biomed.ac.uk/projects-2/for-students/

APPLICATIONS OPEN ON 25 SEPTEMBER AND CLOSE AT 17:00 ON 24 NOVEMBER 2017.

You do NOT need to apply to the University of Bath at this stage – only those applicants who are successful in obtaining an offer of funding from the DTP will be required to submit an application to study at Bath.