It is well established that inflammation and oxidative stress are key components of the pathology of Alzheimer's disease (AD), but how early in the pathological cascade these processes are involved or which specific molecular components are key, has not been fully elucidated. This paper describes the pharmacological approach to understand the molecular components of inflammation and oxidative stress on the activation of microglial cells and neuronal cell viability. We have shown that activation of microglia with the 42-amino-acid form of the ϐ-amyloid peptide (Aϐ42) activates the production of cyclooxygenase-2, the inducible form of nitric oxide synthase and tumour necrosis factor-α and there appears to be little interactive feedback between these three mediators. Moreover, we explore the effects of a series of salen-manganese complexes, EUK-8, -134 and -189, which are known to possess both superoxide and catalase activity. These compounds are able to protect cells from insults produced by hydrogen peroxide or peroxynitrite. Moreover, EUK-134 was also able to limit the output of prostaglandin E2 from activated microglial cells. The mechanisms underlying these effects are discussed. Together, these data support a pivotal role for oxidative stress and inflammation as key mediators of the pathological cascade in AD and provide some ideas about possible therapeutic targets.
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February 2001
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Conference Article|
February 01 2001
Oxidative signalling and inflammatory pathways in Alzheimer's disease
Ian Anderson;
Ian Anderson
*Cambridge Antibody Technology Ltd., The Science Park, Melbourn SG8 6JJ, U.K.
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Christy Adinolfi;
Christy Adinolfi
†Eukarion, Inc., 6F Alfred Circle, Bedford, MA 01739, U.S.A.
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Susan Doctrow;
Susan Doctrow
†Eukarion, Inc., 6F Alfred Circle, Bedford, MA 01739, U.S.A.
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Karl Huffman;
Karl Huffman
†Eukarion, Inc., 6F Alfred Circle, Bedford, MA 01739, U.S.A.
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Ken A. Joy;
Ken A. Joy
‡Department of Neuroscience, GlaxoWellcome Medicines Research Centre, Gunnel's Wood Road, Stevenage SG1 2NY, U.K.
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Bernard Malfroy;
Bernard Malfroy
†Eukarion, Inc., 6F Alfred Circle, Bedford, MA 01739, U.S.A.
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Peter Soden;
Peter Soden
‡Department of Neuroscience, GlaxoWellcome Medicines Research Centre, Gunnel's Wood Road, Stevenage SG1 2NY, U.K.
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H. Tom Rupniak;
H. Tom Rupniak
‡Department of Neuroscience, GlaxoWellcome Medicines Research Centre, Gunnel's Wood Road, Stevenage SG1 2NY, U.K.
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Julie C. Barnes
Julie C. Barnes
1
‡Department of Neuroscience, GlaxoWellcome Medicines Research Centre, Gunnel's Wood Road, Stevenage SG1 2NY, U.K.
1To whom correspondence should be addressed.
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Publisher: Portland Press Ltd
Online ISSN: 1744-1439
Print ISSN: 0067-8694
© 2001 The Biochemical Society
2001
Biochem Soc Symp (2001) 67: 141–149.
Citation
Cora O'Neill, Brian Anderton, Ian Anderson, Christy Adinolfi, Susan Doctrow, Karl Huffman, Ken A. Joy, Bernard Malfroy, Peter Soden, H. Tom Rupniak, Julie C. Barnes; Oxidative signalling and inflammatory pathways in Alzheimer's disease. Biochem Soc Symp 1 February 2001; 67 141–149. doi: https://doi.org/10.1042/bss0670141
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