Oxidative stress induced mitochondrial failure and cellular hypoperfusion: Implication in the pathogenesis of Alzheimer disease

Alzheimer disease (AD) and cerebrovascular accidents (CVAs) are two leading causes of age-related dementia. Increasing evidence supports the notion that chronic hypoperfusion is primarily responsible for the pathogenesis that underlies both disease processes. In this regard, hypoperfusion appears to induce oxidative stress, which is largely due to the formation of reactive oxygen species (ROS). Oxidative stress in brain microvessels and/or parenchymal cells results in an accumulation of ROS, thus promoting leukocyte adhesion and increasing endothelial permeability. The chronic injury results in progressive cellular hypometabolism, which is responsible for AD and CVAs, and appear to be a central initiating factor for vascular abnormality, mitochondrial damage and an imbalance in the activity of vasoactive substances such as different isoforms of nitric oxide synthase (NOS), endothelin-1 (ET-1), oxidative stress markers, mtDNA and mitochondrial enzymes in the vascular wall and in brain parenchymal cells. Here we outline recent evidence, as well as our own experimental data, indicating that chronic injury-stimulus induces hypoperfusion in the microcirculation of vulnerable brain regions which leads to energy failure. This energy failure is manifested by damaged mitochondrial ultrastructure, formation of a large number of non-mature or "young" electron dense "hypoxic" mitochondria and overexpression of mitochondrial DNA (mtDNA) deletions. Additionally, these mitochondrial abnormalities coexist with increased redox metal activity, overexpression of lipid peroxidation markers and RNA oxidation, known to elucidated the oxidative stress that occurs within various cellular compartments and most notably in the vascular endothelium that is associated with atherosclerotic damage. The ultrastructural pathology in the neurovascular regions co-exists with neuronal and glial damage, known to be important in the development of AD. Vulnerable neurons and glial cells show mtDNA deletions and overexpression of oxidative stress markers in regions that only closely associate with damaged vessels. This evidence strongly suggests that chronic hypoperfusion induces the accumulation of the oxidative stress products. Moreover, the degree of vascular wall cell lesions in AD brains is proportional to the degree of neuronal and glial cell damage. We hypothesize that continuous accumulation of oxidative stress products, such as peroxynitrite and large amounts of nitric oxide (NO) generated by the overexpression of the inducible and/or neuronal NO synthase (iNOS and nNOS, respectively), appear to be secondary but accelerating factors for damage and for compromising the blood brain barrier (BBB) in hypoxia/hypoperfusion or AD. Our hypothesis is that pharmacological intervention targeted towards correcting chronic hypoperfusion will change the natural history of the dementing neurodegeneration. Therefore, eliminating this imbalance can be used as a alternate strategy for the treatment of AD.