It is well established that the intracellular accumulation of Aβ (amyloid β-peptide) is associated with AD (Alzheimer's disease) and that this accumulation is toxic to neurons. The precise mechanism by which this toxicity occurs is not well understood; however, identifying the causes of this toxicity is an essential step towards developing treatments for AD. One intracellular location where the accumulation of Aβ can have a major effect is within mitochondria, where mitochondrial proteins have been identified that act as binding sites for Aβ, and when binding occurs, a toxic response results. At one of these identified sites, an enzyme known as ABAD (amyloid-binding alcohol dehydrogenase), we have identified changes in gene expression in the brain cortex, following Aβ accumulation within mitochondria. Specifically, we have identified two proteins that are up-regulated not only in the brains of transgenic animal models of AD but also in those of human sufferers. The increased expression of these proteins demonstrates the complex and counteracting pathways that are activated in AD. Previous studies have identified approximate contact sites between ABAD and Aβ; on basis of these observations, we have shown that by using a modified peptide approach it is possible to reverse the expression of these two proteins in living transgenic animals and also to recover mitochondrial and behavioural deficits. This indicates that the ABAD–Aβ interaction is potentially an interesting target for therapeutic intervention. To explore this further we used a fluorescing substrate mimic to measure the activity of ABAD within living cells, and in addition we have identified chemical fragments that bind to ABAD, using a thermal shift assay.
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August 2011
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Conference Article|
July 20 2011
Mitochondrial β-amyloid in Alzheimer's disease
Eva Borger;
Eva Borger
*School of Biology, Biological and Medical Sciences Building, University of St Andrews, North Haugh, St Andrews, Fife KY16 9TF, U.K.
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Laura Aitken;
Laura Aitken
*School of Biology, Biological and Medical Sciences Building, University of St Andrews, North Haugh, St Andrews, Fife KY16 9TF, U.K.
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Kirsty E.A. Muirhead;
Kirsty E.A. Muirhead
*School of Biology, Biological and Medical Sciences Building, University of St Andrews, North Haugh, St Andrews, Fife KY16 9TF, U.K.
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Zoe E. Allen;
Zoe E. Allen
*School of Biology, Biological and Medical Sciences Building, University of St Andrews, North Haugh, St Andrews, Fife KY16 9TF, U.K.
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James A. Ainge;
James A. Ainge
†School of Psychology, St. Mary's College, University of St Andrews, South Street, St Andrews, Fife KY16 9JP, U.K.
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Stuart J. Conway;
Stuart J. Conway
‡Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
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Frank J. Gunn-Moore
Frank J. Gunn-Moore
1
*School of Biology, Biological and Medical Sciences Building, University of St Andrews, North Haugh, St Andrews, Fife KY16 9TF, U.K.
1To whom correspondence should be addressed (email fjg1@st-andrews.ac.uk).
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Publisher: Portland Press Ltd
Received:
December 06 2010
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem Soc Trans (2011) 39 (4): 868–873.
Article history
Received:
December 06 2010
Citation
Eva Borger, Laura Aitken, Kirsty E.A. Muirhead, Zoe E. Allen, James A. Ainge, Stuart J. Conway, Frank J. Gunn-Moore; Mitochondrial β-amyloid in Alzheimer's disease. Biochem Soc Trans 1 August 2011; 39 (4): 868–873. doi: https://doi.org/10.1042/BST0390868
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