Oxidative Stress Mediated Mitochondrial and Vascular Lesions as Markers in the Pathogenesis of Alzheimer Disease

Abstract

Mitochondrial dysfunction plausibly underlies the aging-associated brain degeneration. Mitochondria play a pivotal role in cellular bioenergetics and cell-survival. Oxidative stress consequent to chronic hypoperfusion induces mitochondrial damage, which is implicated as the primary cause of cerebrovascular accidents (CVA) mediated Alzheimer's disease (AD). The mitochondrial function deteriorates with aging, and the mitochondrial damage correlates with increased intracellular production of oxidants and pro-oxidants. The prolonged oxidative stress and the resultant hypoperfusion in the brain tissues stimulate the expression of nitric oxide synthase (NOS) enzymes, which further drives the formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The ROS and RNS collectively contributes to the dysfunction of the blood-brain barrier (BBB) and damage to the brain parenchymal cells. Delineating the molecular mechanisms of these processes may provide clues for the novel therapeutic targets for CVA and AD patients.

Vascular dysfunction in the pathogenesis of Alzheimer's disease — A review of endothelium-mediated mechanisms and ensuing vicious circles

“…Lipids and proteins in the inner mitochondrial membrane are highly susceptible to ROS, and lipid peroxidation has been observed in oxidative injury [187,195]. Damage to the inner membrane proteins and/or lipids can result in membrane depolarization and impaired mitochondrial function [82].…”

“…In the AD brain, oxidative injury has been demonstrated in mitochondria of neuronal [82,187,196], and also in vascular (endothelial) and perivascular cells [72,89,197]. Cellular energy failure is demonstrated in the AD brain by post mortem studies showing deterioration of mitochondrial ultrastructure, formation of non-mature mitochondria ("hypoxic mitochondria" [72,89]) and excessive mtDNA deletions [72,195].…”

The Role of Inflammatory Mediators in the Pathogenesis of Alzheimer’s Disease

“…Moreover, it has been shown that ROS is potentially toxic and may damage the proteins, lipids and nucleic acids of brain cells and mitochondria, including neurons and oligodendrocytes that may mediate toxicity. 88,89 Generation of ROS is controlled by sensitive genes called vitagenes. These genes encode proteins such as heat shock proteins, nutritional antioxidants which play a neuroprotective role.…”

Age-related macular degeneration and Alzheimer disease

“…Recent reviews claimed that accumulating evidence shows that the key factor in Alzheimer disease is oxidative stress (30,37).…”