Mitochondria DNA deletions in atherosclerotic hypoperfused brain microvessels as a primary target for the development of Alzheimer's disease.

The pathogenesis, which is primarily responsible for Alzheimer's disease (AD) and cerebrovascular accidents (CVA), seems to involve chronic hypoperfusion. The role of hypoperfusion, as a key factor for vascular lesions that causes oxidative stress, appears to be widely accepted as an initiator of AD. Specifically, accumulated oxidative stress increases vascular endothelial permeability and promotes leukocyte adhesions, which is coupled with alterations in endothelial signal transduction and redox-regulated transcription factors. Based on these recent findings, we hypothesize that the cellular and molecular mechanisms by which hypoperfusion-induced reactive oxygen species (ROS) accumulation impairs endothelial barrier function and promotes leukocyte adhesion induces alterations in normal vascular function and results in the development of AD. We are theorizing that mitochondria play a key role in the generation of ROS, resulting in oxidative damage to neuronal cell bodies, as well as other cellular compartment in the AD brain. All of these changes have been found to accompany AD pathology. We have studied the ultrastructural features of vascular lesions and mitochondria in brain vascular wall cells from human AD, yeast artificial chromosome (YAC) and C57B6/SJL transgenic positive (Tg+) mice overexpressing amyloid beta precursor protein (AbetaPP). In situ hybridization using mitochondrial DNA (mtDNA) probes for human wild and 5 kb deleted types and mouse types was performed along with immunocytochemistry using antibodies against amyloid precursor protein (APP), 8-hydroxy-2'-guanosine (8-OHG) and cytochrome c oxidase (COX). There was a higher degree of amyloid deposition, overexpression of oxidative stress markers, mitochondria DNA deletion and mitochondrial structural abnormality in the vascular walls of the human AD, YAC and C57B6/SJL Tg (+) mice compared to age-matched controls. Therefore, selective pharmacological intervention, directed for abolishing the chronic hypoperfusion state, would possibly change the natural course of development of dementing neurodegeneration.

Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in aged transgenic mice.

We have studied the ultrastructural features of vascular lesions and mitochondria in brain vascular wall cells from human AD brain biopsy, human short postmortem brain tissues, and yeast artificial chromosome (YAC) and C57B6/SJL transgenic positive (Tg+) mice overexpressing amyloid beta precursor protein (AbetaPP). In situ hybridization using mitochondrial DNA (mtDNA) probes for human wild type, 5 kb deleted, and mouse mtDNA was performed, along with immunocytochemistry using antibodies against amyloid precursor protein (APP), 8-hydroxy-2'-guanosine (8-OHG), and cytochrome c oxidase (COX). There was a higher degree of amyloid deposition in the vascular walls of the human AD, YAC, and C57B6/SJL Tg (+) mice compared to age-matched controls. In addition, vessels with more severe lesions showed immunopositive staining for APP and possessed large, lipid-laden vacuoles in the cytoplasm of endothelial cells (EC). Significantly more mitochondrial abnormalities were seen in human AD, YAC, and C57B6/SJL Tg (+) mouse microvessels where lesions occurred. In situ hybridization using wild and chimera (5 kb) mtDNA probes revealed positive signals in damaged mitochondria from the vascular endothelium and in perivascular cells of lesioned microvessels close to regions of large amyloid deposition. These features were absent in undamaged regions of human AD tissues, YAC and C57B6/SJL Tg (+) mouse tissues, and in age-matched control subjects. In addition, vessels with atherosclerotic lesions revealed endothelium and perivascular cells possessing clusters of wild and deleted mtDNA positive probes. These mtDNA deletions were accompanied by increased amounts of immunoreactive APP, 8-OHG, and COX in the same cellular compartment. Our observations demonstrate that vascular wall cells, especially their mitochondria, appear to be a central target for oxidative stress-induced damage.

Mitochondria and vascular lesions as a central target for the development of Alzheimer's disease and Alzheimer disease-like pathology in transgenic mice.

Accumulating evidence strongly suggests that the AD brain is characterized by impairments in energy metabolism, and vascular hypoperfusion, whereby oxidative stress appears to be an especially important contributor to neuronal death and development of AD pathology. We hypothesized that mitochondria play a key role in the generation of reactive oxygen species, resulting in oxidative damage to neuronal cell bodies, as well as other cellular compartments in the AD brain. All of these changes have been found to accompany AD pathology. In this review we have outlined recent evidence from the literature and our own original studies concerning the role of mitochondrial abnormalities and vascular damage in the pathogenesis of AD and AD-like pathology in transgenic mice (as a model for human AD). We examined ultrastructural features of vascular lesions and mitochondria from vascular wall cells in human AD brain biopsies, in human short post-mortem brain tissues and in yeast artificial chromosome (YAC) and C57B6/SJL transgenic positive (Tg+) mice overexpressing amyloid beta precursor protein (A beta PP). In situ hybridization using mitochondrial DNA (mtDNA) probes for human wild type, 5kb deleted and mouse mtDNA was performed along with immunocytochemistry using antibodies against amyloid beta precursor protein (A beta PP), 8-hydroxy-2'-guanosine (8OHG) and cytochrome C oxidase (COX) were studied at the electron microscopic levels. There was a higher degree of amyloid deposition in the vascular walls of the human AD, YAC and C57B6/SJL Tg(+) mice compared to aged-matched controls. In addition, vessels with more severe lesions showed immunopositive staining for APP and possessed large, lipid-laden vacuoles in the cytoplasm of endothelial cells (EC). Significantly more mitochondrial abnormalities were seen in human AD, YAC and C57B6/SJL Tg(+) mouse microvessels where lesions occurred. In situ hybridization using wild and chimera (5 kB) mtDNA probes revealed positive signals in damaged mitochondria from the vascular endothelium and in perivascular cells of lesioned microvessels close to regions of large amyloid deposition. These features were absent in undamaged regions of human AD tissues, YAC and C57B6/SJL Tg(+) mouse tissues and in aged-matched control subjects. In addition, vessels with atherosclerotic lesions revealed endothelium and perivascular cells possessing clusters of wild and deleted mtDNA positive probes. These mtDNA deletions were accompanied by increased amounts of immunoreactive APP, 8OHG and COX in the same cellular compartment. Our observations first time demonstrate that vascular wall cells, especially their mitochondria, appear to be a central target for oxidative stress induced damage.

Is nitric oxide a key target in the pathogenesis of brain lesions during the development of Alzheimer's disease?

Nitric oxide (NO) is a short-life key bioregulatory active molecule in the cardiovascular, immune and nervous systems. NO is synthesized by converting L-arginine to L-citrulline by enzymes called NO synthase (NOS). The growing body of evidence strongly supports the theory that this molecule appears to be one of the key targets for the disruption of normal brain homeostasis, which causes the development of brain lesions and pathology such as in Alzheimer's disease (AD) or other related dementia. The vascular content of NO activity appears especially to be a main contributor to this pathology before the over-expression of other NOS isoforms activity in a different brain cellular compartment. We speculate that pharmacological intervention using NO donors and/or NO suppressors will be able to delay or minimize the development of brain pathology and further progression of mental retardation.

The role of nitric oxide in the pathogenesis of brain lesions during the development of Alzheimer's disease.

Nitric oxide (NO) is a key bioregulatory active molecule in the cardiovascular, immune and nervous systems, synthesized through converting L-arginine to L-citrulline by NO synthase (NOS). Research exploration supports the theory that this molecule appears to be one of the key factors for the disruption of normal brain homeostasis, which causes the development of brain lesions and pathology such as in Alzheimer's disease (AD). Especially the vascular content of NO activity appears to be a major contributor to this pathology before the overexpression of NOS activity in other brain cellullar compartments develop. We theorize that pharmacological intervention using NO donors and/or NO suppressors should delay or minimize brain lesion development and further progression of brain pathology and dementia.