Thomas, Rhian - Cardiff University - School of Pharmacy and Pharmaceutical Sciences

个人简介

Qualifications PhD Biosciences, Cardiff University

研究领域

Alzheimer's disease Antibody based therapies Underlying mechanisms of disease My research has been directed at two main areas: cell signalling in disease and amyloid production in Alzheimer’s disease (AD). There are two characteristic neuropathological features of AD, neurofibriallary tangles made of hyperphosphorylated tau and extracellular senile plaques made primarily of amyloid-beta, a 40-43 amino acid peptide produced from amyloid precursor protein (APP). An increase in amyloid-beta levels (especially amyloid-beta 42) is thought to be crucial for the pathogenesis of AD. Amyloid-beta is produced from the protein APP by cleavage events involving the enzymes beta- and gama-secretase which cleave APP sequentially to liberate amyloid-beta. Since the discovery of beta-secretase, an aspartic protease called beta-site APP-cleaving enzyme (BACE1) in 1999, there has been much interest in developing inhibitors. My primary focus has been on investigating how amyloid-beta is produced in Alzheimer’s disease, what affects this and developing therapies to influence this. Our laboratory is interested in developing novel therapeutic antibodies for AD that inhibit amyloid-beta. The antibodies I developed were unusual in that, rather than raising antibodies to amyloid-beta or BACE, the antibodies were raised to APP itself, in the vicinity of the BACE cleavage site. We demonstrated these antibodies successfully reduced amyloid-beta secretion from human cell lines and are now elucidating their effects in vivo. My current interests include the understanding of amyloid-beta generation, particularly in relation to the role of clathrin-dependent and -independent endocytosis. I am currently involved with investigating how caveolin proteins contribute to the generation of this peptide and affect APP metabolism. There is growing evidence to link the caveolin proteins involved in non-clathrin-dependent endocytosis to various aspects of AD, since some studies have reported higher levels in diseased brain tissue. The mechanisms behind this are, however, unclear and our laboratory has a project funded by BRACE (Bristol Research into Alzheimer’s and Care of the Elderly) which aims to clarify this situation. Our data suggests that caveolins may actually sequester APP away from amyloid producing enzymes and hence reduce amyloid levels. In a related piece of work, I have identified important changes in the levels of endocytic-related proteins in the brains of Tg2576 transgenic models of AD. We have now extended these areas of investigation and been funded by BRACE to look at clinical samples of human brain tissue, comparing changes in endocytic proteins in normal ageing with AD.

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Thomas, R.et al. 2016. Decreasing the expression of PICALM reduces endocytosis and the activity of β-secretase: implications for Alzheimer's disease. BMC Neuroscience 17(50) (10.1186/s12868-016-0288-1) pdf Lowe, A.et al. 2015. Lipopolysaccharide exacerbates functional and inflammatory responses to ovalbumin and decreases sensitivity to inhaled fluticasone propionate in a guinea-pig model of asthma. British Journal of Pharmacology 172(10), pp. 2588-2603. (10.1111/bph.13080) pdf Thomas, R. S. and Kidd, E. J. 2014. Caveolin-1 alters the amyloidogenic processing of amyloid precursor protein to amyloid-beta. Neuroreport -Oxford- 25(3), pp. 162-162. (10.1097/01.wnr.0000443076.61006.22) pdf Kidd, E. J., Hvoslef-Eide, M. and Thomas, R. S. 2014. Anti-amyloid precursor protein antibodies as a potential therapy for Alzheimer's disease [Abstract]. Neuroreport 25(3), pp. 145-145. (10.1097/01.wnr.0000443076.61006.22) pdf Thomas, R.et al. 2013. Inhibition of amyloid-[beta] production by anti-amyloid precursor protein antibodies in primary mouse cortical neurones. NeuroReport 24(18), pp. 1058-1061. (10.1097/WNR.0000000000000055) Blain, E. J., Thomas, R. S. and Duance, V. C. 2012. Effect of Wnt3A on load-induced markers of chondrocyte matrix metabolism. International Journal of Experimental Pathology 93(4), pp. A13-A14. (10.1111/j.1365-2613.2012.00822.x) Thomas, R.et al. 2011. Clathrin-mediated endocytic proteins are upregulated in the cortex of the Tg2576 mouse model of Alzheimer's disease-like amyloid pathology. Biochemical and Biophysical Research Communications 415(4), pp. 656-661. (10.1016/j.bbrc.2011.10.131) Lelos, M.et al. 2011. Outcome-specific satiety reveals a deficit in context-outcome, but not stimulus-or action-outcome, associations in aged Tg2576 mice. Behavioral Neuroscience 125(3), pp. 412-425. (10.1037/a0023415) Thomas, R. S., Liddell, J. E. and Kidd, E. J. 2011. Anti-amyloid precursor protein immunoglobulins inhibit amyloid-β production by steric hindrance. Febs Journal 278(1), pp. 167-178. (10.1111/j.1742-4658.2010.07942.x) Thomas, R.et al. 2011. Effects of Wnt3A and mechanical load on cartilage chondrocyte homeostasis. Arthritis Research and Therapy 13(6), article number: R203. (10.1186/ar3536) pdf Thomas, R.et al. 2006. An antibody to the β-secretase cleavage site on amyloid-β-protein precursor inhibits amyloid-β production. Journal of Alzheimer's Disease 10(4), pp. 379-390.