Oxidative stress and neurodegeneration: An inevitable consequence of aging? Implications for therapy

Abstract

Brain aging is one of the most complex issues confronting researchers in neuroscience today. Nevertheless, research on the molecular biology of neurodegenerative disorders, particularly Alzheimer disease, has provided enormous progress in understanding the mechanisms that ultimately lead to the neuronal and glial malfunctions that ultimately damage neurons resulting in death. In this regard, one of the most compelling theories providing a basis for understanding aging and neurodegeneration posits oxidative stress, which results from an accumulation of free radicals in the cell that originates from the intense oxidative metabolism in the central nervous system and the diminished antioxidant defenses, as a major contributor. Here we review evidence demonstrating a robust relationship-epidemiological-clinical, molecular-neurobiological, and pathogenetic-between brain senility, mild cognitive impairment, and Alzheimer disease (as well as other neurodegenerative conditions) that places oxidative stress at a pivotal point in these three neurophysiologic and neuropathologic processes. These observations suggest that the three conditions are steps in the progressive decline in cognitive function. First, we focus on classical, clinical, and psychiatric observations of the cognitive ability of elderly people, from normal functioning to declines associated with aging, and then move to mild and severe pathological impairment, with continually worsening clinical and neuropsychiatric status. We show that the term senile dementia, today removed from the nosological categories, is in fact representative of the clinical observations of progressive age-related brain deterioration. Second, we address oxidative stress and describe the new neurochemical and neuropathological theories of disease pathogenesis, that implicate oxidative stress as the earliest process in brain aging and neurodegeneration in Alzheimer disease. Moreover, we discuss the evidence that amyloid-β, senile plaques, and neurofibrillary tangles may comprise a compensatory defense mechanism against oxidative stress. In addition, the oxidative stress-amyloid-β cascade that develops during Alzheimer disease is also described, in which amyloid formation in the brain further exposes neurons to oxidative stress, eliciting a full neurodegenerative response. Finally, we explore how current treatments of Alzheimer disease, such as acetylcholinesterase inhibitors and non-specific glutamate receptor inhibitors/antagonists, may benefit from the inclusion of antioxidants or metabolic agents that target brain aging, mild cognitive impairment, Alzheimer disease, and other neurodegenerative diseases.