M.A. Smith, X. Zhu, G. Casadesus, G. Aliev, O. Ogawa, A. Nunomura, A. Takeda, J.A. Joseph, R.B. Petersen, G. Perry

Evidence supporting a proximal role for oxidative stress in the pathogenesis Alzheimer disease (AD) led us to investigate the causes and consequences of oxidative stress, which, along the way, led to a number of surprising findings concerning disease pathogenesis.

Causes: Considering that oxidative damage in the brains of AD-affected individuals occurs predominantly within the neuronal cell bodies, we investigated abnormalities that may initiate and promote neuronal oxidative damage. We found a synergistic interplay between mitochondrial abnormalities and redox metal imbalance.

Consequences: The JNK/SAPK and p38 pathways are the major signaling cascades that respond to oxidative stress and activated JNK/SAPK and p38 can phosphorylate tau in a manner similar to that found in AD. Therefore, it is particularly significant that we found that the entire JNK/SAPK and p38 pathways are activated in vulnerable neurons in AD but not control cases.

Surprises: Amyloid-beta and tau, the major components of senile plaques and neurofibrillary tangles, respectively, have historically been considered central mediators of the pathogenesis of AD. However, rather than initiating disease pathogenesis, both lesions occur as a consequence of oxidative stress and are relatively late events. Moreover, there is increasing evidence that these lesions, rather than mediating pathogenesis, function as a primary line of antioxidant defense in both the aged and diseased brain. This notion is supported by the observation that the increased sensitivity to oxidative stress in the aged brain, even in control individuals, is invariably marked by the appearance of both amyloid-betaand tau. Additionally, in AD, where persistent, chronic oxidative stress is superimposed upon an age-related vulnerable environment, one would predict, and in fact we find, an increased lesion load. The notion that amyloid-beta and tau function as protective components brings into serious question the rationale of current therapeutic efforts targeted toward lesion removal.

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