INTRODUCTION O XIDATIVE STRESS entails breaching oxidant defenses to an extent that is sufficient to lead to damage. However, given the dynamic nature of homeostatic systems in response to external insults, increases in oxidative damage do not nec- essarily suggest that the cell is succumbing to oxidative stress and its sequelae. This observation is especially true in neuro- degenerative diseases. The neurons that experience increased oxidative damage, by their continued existence inherently tes- tify that adaptations are reached as a consequence of expo- sure to reactive oxygen species (ROS). This is also the case for Alzheimer disease (AD), where those neurons that exhibit oxidative damage are also associated with induced antioxi- dant systems. Therefore, a prominent role must also be played in AD by the distinct biochemical changes that are associated with, and considered part of, the spectrum of disease, such as the activation of stress-activated protein kinase (SAPK) path- ways and downstream events. MITOCHONDRIALALTERATIONS As the primary site of oxidative bioenergetics within the cell, the mitochondria contribute significantly to oxidative damage and related events. However, extensive evidence indi- cates that cerebral metabolism is reduced in AD (2). These conflicting observations confuse the role of mitochondria in AD (40, 41). It has been reported that activities of specific mi- tochondrial enzyme complexes are reduced in AD, including cytochromeoxidase (COX), the pyruvatedehydrogenase com- 571 1 Institute of Pathology, Case Western Reserve University, Cleveland, OH, U.S.A. 2 Department of Psychiatry and Neurology, Asahikawa Medical College, Asahikawa, Japan. 3 Department of Neurosciences, University of Genova, Genova, Italy. Forum Mini Review Oxidative Stress and Neuronal Adaptation in Alzheimer Disease: The Role of SAPK Pathways XIONGWEI ZHU, 1 ARUN K. RAINA, 1 HYOUNG-GON LEE, 1 MARK CHAO, 1 AKIHIKO NUNOMURA, 2 MASSIMO TABATON, 3 ROBERT B. PETERSEN, 1 GEORGE PERRY, 1 and MARK A. SMITH 1 ABSTRACT Recent evidence indicates that oxidative stress occurs early in the progression of Alzheimer disease, signifi- cantly before the development of the hallmark pathologies, namely neurofibrillary tangles and senile plaques. The interaction of abnormal mitochondria, redox transition metals, and oxidative stress response elements contributes to the generation of reactive oxygen species in diseased neurons. Oxidative damage to major cellu- lar molecules is seen in a number of disease states that are either acute or chronic and it is apparent that with- out eliciting compensations that restore redox balance, cells will rapidly succumb to death. Indeed, although oxidative stress is a prominent feature in Alzheimer disease, few vulnerable neurons show clear signs of apop- tosis, suggesting that the level of oxidative stress does not significantly exceed neuronal oxidative defenses. In light of this observation, we propose that neurons in Alzheimer disease are exposed to low, but chronic, levels of oxidative stress that lead neurons to elicit adaptive responses such as the activation of stress-activated pro- tein kinase pathways. Antioxid. Redox Signal. 5, 571–576. ANTIOXIDANTS & REDOX SIGNALING Volume 5, Number 5, 2003 © Mary Ann Liebert, Inc.