SIGNALING OXIDATIVE STRESS IN ALZHEIMER DISEASE





Xiongwei Zhu, Osamu Ogawa, Craig S. Atwood, George Perry, Mark A. Smith*

Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106 USA



The temporal association between oxidative stress and the hallmark pathologies of Alzheimer disease (AD) demonstrates that oxidative stress is among the earliest events in the disease. Nonetheless, neither the consequence of oxidative stress nor how oxidative stress relates to other pathological features of the disease are clear at this point. To begin to address these issues, we investigated the mitogen-activated protein kinase pathways, namely ERK, JNK and p38 pathways, in the pathogenesis of AD. In affected brain regions of individuals with AD, p38 kinase is abnormally activated and associated with neurofibrillary pathologies. By marked contrast, these brain regions exhibit a low level of diffuse p38 kinase in age-matched controls. The distribution and activation pattern of the upstream activator of p38, namely MKK6, is also altered in AD compared to control brain, suggesting that the entire p38 pathway is activated. Similarly, ERK and JNK pathways are also abnormally activated in AD.

Given the complete overlap between p38 kinase and tau-positive neurofibrillary pathology in situ, we suspect that p38 may play a key role in disease pathogenesis. To explore this further, co-immunoprecipitation and dot blot assays indicated that the p38 kinase and tau are physically associated and thereby p38 is a likely candidate kinase for the phosphorylation of tau in vivo. Finally, since amyloid-á is thought to be the causative factor for the pathogenesis of AD and amyloid-á can act as an oxidative stressor, we suspected that amyloid-á may be responsible for the activation of MAPK pathways. To investigate this possibility, using human M17 neuroblastoma and rat cortical primary neurons, we found that fibrillized amyloid-á induced the activation of ERK, JNK and p38 in a dose- and time-dependent manner, and, most importantly, that the activation of these kinases mediated amyloid-á-induced cell death.

Taken together, these data indicate that oxidative stress-induced downstream events, mediated via MAPK pathways, could play a key role in disease pathogenesis. MAPK pathways can be the new targets for interrupting the disease.




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