Acceso usuarios
Gjumrakch Aliev, Joséph Charles Lamanna, Luis Morales, Mark Eric Obrenovich, Gerardo Jesús Pacheco, Héctor Palacios Gerona, Eldar Qasimov, Brianna Walrafen
Alzheimer disease and cerebrovascular accident are two leading causes of age-related dementia. Increasing evidence supports the idea that chronic hypoperfusion is primarily responsible for the pathogenesis that underlies both disease processes. Hypoperfusion is associated with oxidative imbalance, largely due to reactive oxygen species, which is associated with other age-related degenerative disorders. Recent evidence indicates that a chronic injury stimulus induces the hypoperfusion seen in the microcirculation of vulnerable regions of the brain. This leads to energy failure, manifested by damaged mitochondrial ultrastructure. Mitochondrial derangements lead to the formation of a large number of electron-dense, ¿hypoxic¿ mitochondria and cause the overproduction of mitochondrial DNA (mtDNA) deletions, which is most likely due to double stranded breaks. Additionally, these mitochondrial abnormalities coexist with increased redox metal activity, lipid peroxidation, and RNA oxidation, all of which are well established features of Alzheimer disease pathology, prior to the appearance of amyloid b deposition. Alzheimer disease, oxidative stress occurs within various cellular compartments and within certain cell types more than others, namely the vascular endothelium, which is associated with atherosclerotic damage, as well as in pyramidal neurons and glia. Interestingly, these vulnerable cells show mtDNA deletions and oxidative stress markers only in the regions that are closely associated with damaged vessels. This evidence strongly suggests that chronic hypoperfusion induces the accumulation of the oxidative stress products. Furthermore, brain vascular wall lesions linearly correlate with the degree of neuronal and glial cell damage. We, therefore, conclude that chronic hypoperfusion is a key initiator of oxidative stress in various brain parenchymal cells, and the mitochondria appear to be primary targets for brain damage in Alzheimer disease. In this manuscript, we outline a role for the continuous accumulation of oxidative stress products, such as an abundance of nitric oxide products (via the overexpression of inducible and/or neuronal NO synthase (iNOS and nNOS respectively) and peroxynitrite accumulation, as secondary but accelerating factors compromising the blood brain barrier (BBB). If this turns out to be the case, pharmacological interventions that target chronic hypoperfusion might ameliorate the key features of dementing neurodegeneration.
Alzheimer disease and cerebrovascular accident are two leading causes of age-related dementia. Increasing evidence supports the idea that chronic hypoperfusion is primarily responsible for the pathogenesis that underlies both disease processes. Hypoperfusion is associated with oxidative imbalance, largely due to reactive oxygen species, which is associated with other age-related degenerative disorders. Recent evidence indicates that a chronic injury stimulus induces the hypoperfusion seen in the microcirculation of vulnerable regions of the brain. This leads to energy failure, manifested by damaged mitochondrial ultrastructure. Mitochondrial derangements lead to the formation of a large number of electron-dense, “hypoxic” mitochondria and cause the overproduction of mitochondrial DNA (mtDNA) deletions, which is most likely due to double stranded breaks. Additionally, these mitochondrial abnormalities coexist with increased redox metal activity, lipid peroxidation, and RNA oxidation, all of which are well established features of Alzheimer disease pathology, prior to the appearance of amyloid b deposition.Alzheimer disease, oxidative stress occurs within various cellular compartments and within certain cell types more than others, namely the vascular endothelium, which is associated with atherosclerotic damage, as well as in pyramidal neurons and glia. Interestingly, these vulnerable cells show mtDNA deletions and oxidative stress markers only in the regions that are closely associated with damaged vessels. This evidence strongly suggests that chronic hypoperfusion induces the accumulation of the oxidative stress products. Furthermore, brain vascular wall lesions linearly correlate with the degree of neuronal and glial cell damage. We, therefore, conclude that chronic hypoperfusion is a key initiator of oxidative stress in various brain parenchymal cells, and the mitochondria appear to be primary targets for brain damage in Alzheimer disease. In this manuscript, we outline a role for the continuous accumulation of oxidative stress products, such as an abundance of nitric oxide products (via the overexpression of inducible and/or neuronal NO synthase (iNOS and nNOS respectively) and peroxynitrite accumulation, as secondary but accelerating factors compromising the blood brain barrier (BBB). If this turns out to be the case, pharmacological interventions that target chronic hypoperfusion might ameliorate the key features of dementing neurodegeneration.
