Oxidative signalling and inflammatory pathways in Alzheimer's disease.
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 beta-amyloid peptide (A beta 42) activates the production of cyclooxygenase-2, the inducible form of nitric oxide synthase and tumour necrosis factor-alpha 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.
Anderson
I
I
Cambridge Antibody Technology Ltd., Science Park, Melbourn SG8 6JJ, U.K.
Adinolfi
C
C
Doctrow
S
S
Huffman
K
K
Joy
K A
KA
Malfroy
B
B
Soden
P
P
Rupniak
H T
HT
Barnes
J C
JC
D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D006801:Humans; D007249:Inflammation / Q000209:etiology; D018836:Inflammation Mediators / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016229:Amyloid beta-Peptides; D018836:Inflammation Mediators; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D015232:Dinoprostone