Dr Robert Williams
Profile
Current Research
Synaptic dysfunction and subsequent neuronal loss is common to all progressive neurodegenerative disorders and accounts for the majority of disease-associated symptoms. Understanding the fundamental signalling mechanisms that regulate synaptic viability and finding ways of maintaining or promoting these pathways is key to the development of new strategies to protect vulnerable cells in the diseased and ageing brain.
APP processing and Alzheimer’s Disease
The generation of amyloid β peptide (Aβ) and its aggregation as soluble oligomers is central to the pathogenesis of Alzheimer’s Disease (AD). Identifying new approaches for reducing Aβ burden either through inhibition of βγ-secretases, stimulation of α-secretase, or by maintaining brain homeostasis is a major therapeutic goal. We are interested in the physiological control of APP processing and have shown that excitatory neurotransmission at glutamatergic synapses suppresses the production of Aβ. Accumulating evidence suggests that pro-oxidant and pro-inflammatory conditions within the brain provide a permissive environment that tips excitatory neurotransmission away from αγ-secretase and towards βγ-secretase-mediated processing of APP and this is the likely trigger for synaptic dysfunction. We are using molecular and cellular approaches to understand the precise mechanisms underlying this pathological switching in APP processing to facilitate the identification and validation of new targets for suppressing Aβ production.
Flavonoids and Alzheimer’s Disease
There is increasing evidence that the consumption of flavonoid-rich foods can beneficially influence normal cognitive function and a growing number of flavonoids have been shown to inhibit the development of AD-like pathology. This appears to be mediated by the direct interactions of flavonoids with a number of cellular targets and does not appear to be simply due to their known antioxidant actions. Specific interactions within MAP kinase and Akt signalling pathways increases the expression of neuroprotective and neuromodulatory proteins. We are exploring these mechanisms further and are screening dietary flavonoids for potential therapeutic utility in dementia.
Publications
Pereira Morais, M. P., Marshall, D., Flower, S. E., Caunt, C. J., James, T. D., Williams, R. J., Waterfield, N. R. and Van Den Elsen, J. M. H., 2013. Analysis of protein glycation using fluorescent phenylboronate gel electrophoresis. Scientific Reports, 3, 1437.
Guadagna, S., Esiri, M. M., Williams, R. J. and Francis, P. T., 2012. Tau phosphorylation in human brain: relationship to behavioral disturbance in dementia. Neurobiology of Aging, 33 (12), pp. 2798-2806.
Bahia, P. K., Pugh, V., Hoyland, K., Hensley, V., Rattray, M. and Williams, R. J., 2012. Neuroprotective effects of phenolic antioxidant tBHQ associate with inhibition of FoxO3a nuclear translocation and activity. Journal of Neurochemistry, 123 (1), pp. 182-191.
McHugh, P. C., Wright, J. A., Williams, R. J. and Brown, D. R., 2012. Prion protein expression alters APP cleavage without interaction with BACE-1. Neurochemistry International, 61 (5), pp. 672-680.
Choudhry, F., Howlett, D. R., Richardson, J. C., Francis, P. T. and Williams, R. J., 2012. Pro-oxidant diet enhances β/γ secretase-mediated APP processing in APP/PS1 transgenic mice. Neurobiology of Aging, 33 (5), pp. 960-968.
Spencer, J. P. E., Vafeiadou, K., Williams, R. J. and Vauzour, D., 2012. Neuroinflammation: Modulation by flavonoids and mechanisms of action. Molecular Aspects of Medicine, 33 (1), pp. 83-97.
Williams, R. J. and Spencer, J. P. E., 2012. Flavonoids, cognition, and dementia: Actions, mechanisms, and potential therapeutic utility for Alzheimer disease. Free Radical Biology & Medicine, 52 (1), pp. 35-45.
Gaeta, A., Molina-Holgado, F., Kong, X. L., Salvage, S., Fakih, S., Francis, P. T., Williams, R. J. and Hider, R. C., 2011. Synthesis, physical-chemical characterisation and biological evaluation of novel 2-amido-3-hydroxypyridin-4(1H)-ones: Iron chelators with the potential for treating Alzheimer's disease. Bioorganic & Medicinal Chemistry, 19 (3), pp. 1285-97.
Thambisetty, M., Simmons, A., Velayudhan, L., Hye, A., Campbell, J., Zhang, Y., Wahlund, L.-O., Westman, E., Guntert, A., Kinsey, A., Proitsi, P., Powell, J., Causevic, M., Killick, R., Lunnon, K., Lynham, S., Broadstock, M., Choudhry, F., Howlett, D., Williams, R., Sharp, S., Mitchlemore, C., Tunnard, C., Leung, R., Foy, C., O'Brien, D., Breen, G., Furney, S., Ward, M., Kloszewska, I., Mecocco, P., Soininen, H., Tsolaki, M., Vellas, B., Hodges, A., Murphy, D., Parkins, S., Richardson, J., Resnik, S., Ferrucci, L., Wong, D., Zhou, Y., Muehlboeck, S., Evans, A., Francis, P., Spenger, C. and Lovestone, S., 2010. Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease. Archives of General Psychiatry, 67 (7), pp. 739-748.
Rainey-Smith, S. R., Andersson, D. A., Williams, R. J. and Rattray, M., 2010. Tumour necrosis factor alpha induces rapid reduction in AMPA receptor-mediated calcium entry in motor neurones by increasing cell surface expression of the GluR2 subunit: relevance to neurodegeneration. Journal of Neurochemistry, 113 (3), pp. 692-703.
Hoey, S. E., Williams, R. J. and Perkinton, M. S., 2009. Synaptic NMDA receptor activation stimulates α-secretase amyloid precursor protein processing and inhibits amyloid-β production. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 29 (14), pp. 4442-4460.
Vafeiadou, K., Vauzour, D., Lee, H. Y., Rodriguez-Mateos, A., Williams, R. J. and Spencer, J. P. E., 2009. The citrus flavanone naringenin inhibits inflammatory signalling in glial cells and protects against neuroinflammatory injury. Archives of Biochemistry and Biophysics, 484 (1), pp. 100-109.
Vafeiadou, K., Vauzour, D., Rodriguez-Mateos, A., Whiteman, M., Williams, R. and Spencer, J., 2008. Glial metabolism of quercetin reduces its neurotoxic potential. Archives of Biochemistry and Biophysics, 478 (2), pp. 195-200.
Bahia, P. K., Rattray, M. and Williams, R. J., 2008. Dietary flavonoid (-)epicatechin stimulates phosphatidylinositol 3-kinase-dependent anti-oxidant response element activity and up-regulates glutathione in cortical astrocytes. Journal of Neurochemistry, 106 (5), pp. 2194-2204.
Abbott, J. J., Howlett, D. R., Francis, P. T. and Williams, R. J., 2008. Aβ1-42 modulation of Akt phosphorylation via α7 nAChR and NMDA receptors. Neurobiology of Aging, 29 (7), pp. 992-1001.
Rainey-Smith, S., Schroetke, L.-W., Bahia, P., Fahmi, A., Skilton, R., Spencer, J. P. E., Rice-Evans, C., Rattray, M. and Williams, R. J., 2008. Neuroprotective effects of hesperetin in mouse primary neurones are independent of CREB activation. Neuroscience Letters, 438 (1), pp. 29-33.
Pezet, S., Marchand, F., D'Mello, R., Grist, J., Clark, A. K., Malcangio, M., Dickenson, A. H., Williams, R. J. and McMahon, S. B., 2008. Phosphatidylinositol 3-kinase is a key mediator of central sensitization in painful inflammatory conditions. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 28 (16), pp. 4261-4270.
Molina-Holgado, F., Gaeta, A., Francis, P. T., Williams, R. J. and Hider, R. C., 2008. Neuroprotective actions of deferiprone in cultured cortical neurones and SHSY-5Y cells. Journal of Neurochemistry, 105 (6), pp. 2466-2476.
