Polyphenols as inhibitors of tau aggregation: protecting the ageing brain

Tau is a microtubule-associated protein that can misfold into toxic inclusions known to be key drivers
in the pathology of Alzheimer's disease. Recent studies at Bath have identified several polyphenolbased molecules that are known to be effective in modulating tau aggregation in vitro, but which lack
the necessary cell penetrance, bioavailability, and potency to further develop the molecules into
useful diagnostics or therapeutics. By using our initial hits as molecular scaffolds, the student will gain
expertise in intracellular high-throughput screening using a small-molecule library to identify
molecules that are capable of binding to tau and modulating amyloid formation and associated
toxicity. Since the screen is undertaken inside living cells it has the additional benefit of being able to
profile for compounds that can traverse biological membranes, that are themselves non-toxic, and
that can abolish tau-associated toxicity that arises from misfolding and aggregation. Moreover, as the
assay relies on correct protein folding and consequent fluorescence readout as a marker of success,
the most effective compounds can be easily and rapidly identified and even quantitatively ranked
according to the greatest levels of fluorescence. The student will be involved with all aspects of the
project including solid-phase peptide synthesis, in vitro aggregation experiments, library screening
assays in both bacterial (Mason, Bath) and mammalian systems (Williams, Bath), expertise in cell
biology using primary neurons, and skills using in silico molecular docking simulations (Sessions,
Bristol). The student will use the above techniques to create both a cellular and molecular
understanding of how the most effective membrane penetrant polyphenols exert their effects; i.e.
where within tau that they bind, the conformation and oligomeric state of tau that is populated, and
how they exert their effect upon downstream markers of toxicity. The latter will help to couple
neuronal cell context with the biophysics of inhibition and toxicity to provide a complete
understanding of how the most effecting compounds work. We envisage that the most effective
molecules will form precursors to drugs for tau-based diseases and as probes to monitor tau
aggregation before symptoms present.