Alzheimer Disease: Oxidative Stress and Compensatory Responses Paula I. Moreira, Akihiko Nunomura, Xiongwei Zhu, Hyoung-Gon Lee, Gjumrakch Aliev, Mark A. Smith, and George Perry Abstract Oxidative stress occurs early in the progression of Alzheimer disease, significantly before the development of the pathologic hallmarks, neurofibril- lary tangles, and senile plaques. All classes of macromolecules are affected by oxidative stress leading, inevitably, to neuronal dysfunction. Extensive data from the literature support the notion that mitochondrial and metal abnorm- alities are key sources of oxidative stress in Alzheimer disease. Furthermore, it has been suggested that in the first stage of the development of Alzheimer disease, amyloid-b deposition and hyperphosphorylated tau function as com- pensatory responses to ensure that neuronal cells do not succumb to oxidative damage. However, during the progression of the disease, the antioxidant activ- ity of both agents evolves into prooxidant activity, resulting in the exacerbation of reactive oxygen species production. Keywords Alzheimer disease  amyloid b-protein  hyperphosphorylated tau protein  metals  mitochondria  oxidative stress 1 Introduction Alzheimer disease (AD) is a progressive, degenerative brain disorder resulting in cognitive and behavioral decline and is the leading cause of dementia in the Western world. Two pathological hallmarks are observed in the brains of AD patients at autopsy: intracellular neurofibrillary tangles and extracellular senile plaques in the neocortex, hippocampus, and other subcortical regions essential for cognitive function [1]. Neurofibrillary tangles are formed from paired helical filaments composed of neurofilaments and hyperphosphorylated tau protein [2]. In turn, plaque cores are formed mostly from deposition of amyloid-b (Ab) peptide that results from the cleavage of the amyloid-b-protein precursor (AbPP). G. Perry (*) Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA e-mail: george.perry@utsa.edu S.C. Veasey (ed.), Oxidative Neural Injury, Contemporary Clinical Neuroscience, DOI 10.1007/978-1-60327-342-8_7, Ó Humana Press, a part of Springer ScienceþBusiness Media, LLC 2009 109