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| First Name: | Brian | | Last Name: | Austen | | Title: | PRofessor | | Advanced Degrees: | MA; PhD | | Affiliation: | St George's Hospital Medical School | | Department: | Basic Medical Sciences | | Street Address 1: | Cranmer Terrace | | Street Address 2: | tooting | | City: | LONDON SW17 ORE | | State/Province: | London | | Zip/Postal Code: | SW17 ORE | Country/Territory: | United Kingdom | | Phone: | 00442087255651 | | Fax: | 00442087253594 | | Email Address: |  |
Disclosure:
(view policy)
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Aging Process, Prion Diseases, Alzheimer Disease
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A-beta PP/A-beta, Molecular and Cell biology, Proteomics, cholesterol, Animal Models, Neurobiology
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Medical hospital, University, Research institute
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Research Brian Austen is a Professor in Protein Science at St George’s Hospital Medical School in south London. With a background in protein/peptide chemistry, he worked for a number of years into mechanisms of intracellular protein targeting. He was one of the first to use photo-crosslinking as means of detecting translocator proteins in the endoplasmic reticulum membrane, and showed that the signal peptide binding subunit of mammalian signal recognition particle functions in bacteria. He has elucidated intracellular trafficking pathways of the amyloid precursor protein, thought to be causative in Alzheimer’s disease, and unravelled a hitherto unknown mechanistic link between raised cholesterol levels and Alzheimer’s disease involving increased deposition of amyloid. This work involved development of a sensitive assay to measure variants of beta-amyloid in biological fluids with Ciphergen, using affinity matrix ProteinArrays and mass spectrometry. In conjunction with CeNeS, he has developed synthetic inhibitors of beta-amyloid fibril formation which prevent neurotoxicity. Other neurotoxic peptides, such as synuclein, Abri and Adan (products of the BRI gene involved in familial British and Danish dementia), known to produce toxic oligomers, are also under study. His research shows that insoluble amyloid fibrils are not the toxic species in these diseases, wheras soluble SDS-stable oligomeric structures are. The challenge of the next few years will be to establish the structure of these soluble species, and define how they kill neurones. It is also proposed to bring the discovery that statins, which inhibit cholesterol biosynthesis, depress amyloid deposition, closer to the clinic. The role of beta-amyloid induced microglial-released inflammatory mediators in destroying neurones in the Alzheimer patients’s brain are under study, and in a collaborative project with Glaxo-Wellcome, cyclic hinge-loop peptides of IgG which bind the
macrophage-specific Fc receptor and have potential as anti-inflammatory agents, have been synthesised.
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Austen B, Christodoulou G, Terry JE. (2002) Relation between Cholesterol levels, Statins and Alzheimer s Disease in the human population. J Nutr Health Aging. 6(6):377-82.
Sidera C, Liu C, Austen BM (2002). Pro-domain removal in ASP-2 and the cleavage of the amyloid precursor are influenced by pH.BMC Biochem. 3(1): [epub ahead of print]
Austen B, El-Agnaf O, Nagala S, Patel B, Gunasekera N, Lee M, Lelyveld V. Properties of neurotoxic peptides related to the BRI gene.Biochem Soc Trans. 2002;30(4):557-9.
Sidera, C and Austen BM 2001)The role of intracellular cholesterol on the Processing of the -amyloid precursor protein. Journal of Nutrition, Health and Ageing. In press.
Sidera C, Liu C and Frimpong-Manso The role of cholesterol in the processing of beta-secretase ASP-2.Proceedings of 2nd Int Conference on Vascular Dementia, Salzburg, Austria Jan 2002 (ed Amos D. Korczyn) Monduzzi-editore Bologna, Italy pp147-153.
El-Agnaf OMA, Nagala, C, Patel, BP and Austen BM (2001) Non-fibrillar Oligomeric Species of the Amyloid Abri Peptide, Implicated in Familial British Dementia are more potent at Inducing Apoptotic CellDeath than Protofibrils or Mature fibrils J Molecular Biology.310; 157-168
El-Agnaf OM, Sheridan JM, Sidera C, Siligardi G, Hussain R, Haris PI, Austen BM. Effect of the disulfide bridge and the C-terminal extension on the oligomerization of the amyloid peptide ABri implicated in Familial British Dementia (2001) Biochemistry. 2001;40(12):3449-57
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Mechanism connecting raised cholesterol with AD |
Isolation of beta-secretase from cholesterol-enriched rafts, and identification of all linked proteins, identification of binding partners, and drug development based on blockage of those interactions that lead to beta-amyloid production. |
Statins reverse the pathology of AD, and should be used to treat patients. |
Dounle-blind placebo controlled clinical trial of statins. |
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