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Oxidative Stress-induced Cellular Hypoperfusion, Mitochondrial Failure and Brain Hypometabolism as the Causative Factors for the Pathophysiology of Cerebrovascular and Alzheimer Disease: Past, Present and Future

Gjumrakch Aliev1, and V. Prakash Reddy2

From the 1School of Health Science and Healthcare Administration, University of Atlanta, Atlanta, GA 30360, USA and 2Department of Chemistry, Missouri University of Science and Technology, Rolla, MO 65409, USA



Abstract: Atherosclerosis and stroke, including cerebrovascular athero- and arteriosclerosis have neurological consequences such as Alzheimer disease (AD) and other neurodegenerative disorders, the leading cause of age-associated disability, dementia and death. Four million people suffer from AD in the United States alone, and this figure will balloon to 16 million persons affected, by the year 2040. Neurodegenerative disorders are characterized by loss of cognitive function and inappropriate death of nerve cells in areas of the brain that control such functions as memory and language. Conventional wisdom thus far is primarily focused on the hypothesis that AD is a ‘neurodegenerative’ disorder caused by: (1) abnormal deposition of “amyloid-β” peptide aggregates as senile plaques in AD brains, (2) intracellular accumulation of neurofibrillary tangles (NFTs), and (3) abnormal cell-cycle re-entry of neuronal cells. The trigger for nerve cell death is unknown in the case of AD. In this hypothesis paper we summarize the causative factors for AD and its often overlooked relation to cerebrovascular diseases.


A rapidly growing body of evidence indicates that increased oxidative stress resulting from reactive oxygen and reactive nitrogen species (ROS and RNS) is associated with the aging process and age-related degenerative disorders such as atherosclerosis, ischemia/reperfusion, arthritis, stroke, and neurodegenerative diseases.[1] The ROS and RNS are generated at the sites of inflammation and injury, and at relatively low concentrations, they can function as signaling species in the regulation of fundamental cell activities such as growth and adaptation responses. At higher concentrations, on the other hand, the ROS/RNS can cause cell injury and death through a variety of pathways including oxidative stress and protein crosslinking.[2,3] The vascular endothelium, which regulates the passage of macromolecules and circulating cells from blood to tissue, is a major target of oxidative stress, playing


a critical role in the pathophysiology of vascular diseases.[4-7] The vascular endothelium, neurons and glia are the principal sites of synthesis, storage and release of ROS/RNS, and related vascular active substances and thus their contribution to the pathophysiology of atherosclerosis, stroke, non-atherosclerotic cerebrovascular disease and neurodegenerative syndromes such as mild cognitive impairment (MCI) and AD is extremely important.[8-10] In addition, abnormalities in cholesterol metabolism, oxidative stress and vascular lesions are important factors contributing to the pathogenesis of AD, stroke and MCI. The latter hypothesis is based on the positive correlations found between stroke, MCI, AD and cardiovascular diseases.[1] New evidence indicates that continuous overproduction of ROS/RNS in concert with decreased antioxidant defenses induces cellular damage.[1,6] Specifically, oxidative stress induces vascular endothelial permeability and promotes leukocyte adhesion, which are coupled with alterations in endothelial signal transduction and redox-regulated transcription factors.[10] Based on this we hypothesize that the cellular and molecular mechanisms, by which cholesterol metabolism abnormalities induce the formation of large amounts of ROS, decrease endothelial barrier function through the overexpression of inducible nitric oxide synthase (iNOS).[7]

Chronic injury stimuli have the effect of inducing decompensation and or alterations in normal vascular function, which results in the development of cerebrovascular arterio- and atherosclerosis that further manifest as stroke, MCI and/or AD.[7] Aliev and coworkers’[4,10-12] recent finding indicates there is an imbalance in the activity of nitric oxide synthase (NOS) isoforms, endothelin-1 (ET-1), oxidative stress markers, mitochondrial DNA (mtDNA) and mitochondrial enzymes in the vascular wall from the large arteries of Watanabe heritable hyperlipidemic (WHHL) rabbits and Yoshida heritable hyperlipidemic (YOS) rats, and in brain parenchymal cells in aged Aβ precursor protein (AβPP) mice. This misbalance augments chronic high cholesterol levels, hypoxia/reperfusion,

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