Signal transduction cascades associated with oxidative stress in Alzheimer's disease.
It has now been established through multiple lines of evidence that oxidative stress is an early event in Alzheimer's disease, occurring prior to the canonical cytopathology. Thus, oxidative stress likely plays a key pathogenic role in the disease and is clearly involved in the cell loss and other neuropathology associated with Alzheimer's disease as demonstrated by the large number of metabolic signs of oxidative stress and by markers of oxidative damage. One puzzling observation, however, is that oxidative damage decreases with disease progression, such that levels of markers of rapidly formed oxidative damage, which are initially elevated, decrease as the disease progresses to advanced Alzheimer's disease. This finding indicates that reactive oxygen species not only cause damage to cellular structures but also provoke cellular responses, such as the compensatory upregulation of antioxidant enzymes found in vulnerable neurons in Alzheimer's disease. Not surprisingly, stress-activated protein kinase pathways, which are activated by oxidative stress, are extensively activated during Alzheimer's disease. In this review, we present the evidence of oxidative stress and compensatory responses that occur in Alzheimer's disease with a particular focus on the roles and mechanism of activation of stress-activated protein kinase pathways.
Petersen
Robert B
RB
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Nunomura
Akihiko
A
Lee
Hyoung-gon
HG
Casadesus
Gemma
G
Perry
George
G
Smith
Mark A
MA
Zhu
Xiongwei
X
D000544:Alzheimer Disease / Q000503:physiopathology*; D001921:Brain / Q000503:physiopathology; D002470:Cell Survival / Q000502:physiology; D018450:Disease Progression; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000502:physiology; D009474:Neurons / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000633:toxicity; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
D017382:Reactive Oxygen Species; D048670:MAP Kinase Kinase 4