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

Abstract

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.

Increase in Glucose-6-Phosphate Dehydrogenase in Adipocytes Stimulates Oxidative Stress and Inflammatory Signals

“…Although oxidative stress is closely associated with inflammatory signals and gene expression through nuclear factor-B (NF-B) signaling (10,11), it is not completely understood how obesity or metabolic disorder states could increase oxidative stress. One of the major sources of cellular reactive oxygen species (ROS) is mitochondria (12), and its dysfunction contributes to several pathological conditions, including vascular complications of diabetes, neurodegenerative diseases, and cellular senescence (13)(14)(15)(16)(17). Furthermore, hyperglycemia and lipotoxicity observed in obesity and its related disorders are associated with mitochondrial dysfunction and generation of oxidative stress (18,19).…”

Cardiovascular Disease Could Be Contained Based on Currently Available Data!

“…Ozone therapy is relatively inexpensive and simpler than a variety of surgical interventions. Therefore, in spite of the possible toxic effects associated with ozone therapy, which is presently being proactively addressed (Tylicki L et al, 2003), decreasing scavenger enzyme activity in individuals with cardiovascular cases can be addressed or restored by appropriate application of ozone autohemotherapy.In agreement with the fact that cardiovascular disease share major pathogenic factors with neurodegenerative disorders such as Alzheimer's disease Aliev et al, 2003;Aliev, 2002;Arlt et al, 2001;Miyakawa, 2002;Skoog and Gustafson, 2002;de La Tore, 2002Berliner and Heinecke, 1996;Mattson and Kroemer, 2003;Sparks, 1997;Newman et al, 2001;Hofman et al, 1997;Bulteau et al, 2001), it is thus conceivable that appropriate application of ozone therapy be ameliorative, under certain conditions, in individuals with Alzheimer's disease, as well.…”

“…Support for this notion explains the puzzle O. N. F. C. Ofodile posed by seemingly unrelated drugs (drugs primarily produced for the management of cardiovascular diseases that confer protection against neurodegenerative pathological conditions (Jones et al, 1999;Tsuschida et al, 1990;Feleszko et al, 1999;Stuve et al, 2003;Teunissen et al, 2003;Zamrini et al, 2004). Furthermore, in agreement with this notion, a large body of evidence implicates free radical toxicity, radical induced perturbation of the ubiquitin-proteasome catalytic pathway (Mayer et al, 1991;Layfieldet al, 2001;Herrmann J et al, 2003), radical induced mutations and oxidative enzyme impairment and mitochondrial dysfunction, and perturbation of the homeostasis of calcium in the brain (Marin-Garcia et al, 2002;Sheehan et al, 1997;Calabrese et al, 2001;Golden and Melov, 2001;Nicholls, 2002;Aliev et al, 2003) in the clinical manifestation of neurodegenerative and cardiovascular diseases. Unregulated accumulation of oxidative damage in neurons and in the cardiac muscles either primarily or secondarily may account for the increased incidence of a variety of neurodegenerative diseases and cardiovascular pathological conditions.…”

“…These investigators, utilizing the mev-1 (Kn1) nematode in their experiments reported that treatment of EUK-134 resulted in extension of Lifespan by over 60%, thereby lending support to the hypothesis that therapeutic employment of EUK-134 causes a decrease in chronic oxidative stress in mev-1 mutant, effectively, normalizing its lifespan to approximate that of the wild type. Thus, the above O. N. F. C. Ofodile described points imply: 1) that age-associated loss of neurological functions in mammals can (could) be partially reversed through the supplementation of antioxidants, 2) apparently age-related decline in cognitive function in humans could be reduced by consuming diets rich in antioxidants or through supplementing diet with appropriate antioxidants, 3) since cardiovascular disease share major pathogenic factors with some aging-associated neurodegenerative disorders such as Alzheimer's disease Aliev et al, 2003;Aliev, 2002;Arlt et al, 2001;Miyakawa, 2002;Skoog and Gustafson,2002;de La Tore, 2002Berliner and Heinecke, 1996;Mattson and Kroemer, 2003;Sparks, 1997;Newman et al, 2001;Hofman et al, 1997;Bulteau et al, 2001), appropriate employment of salen-manganese complexes in the management of cardiovascular disease may be of enormous benefit.…”

“…Despite the fact that cardiovascular disorder is multifactorial in its etiology, nevertheless, there remain some potential for disease prevention and more effective management by employment of various antioxidant agents, and dietary caloric restriction measures, because these measures may play important role in modulating blood lipids and their propensity for oxidation. Cardiovascular disease share various important pathogenic factors with some chronic diseases, which are characterized by dysfunction of ubiquitin-proteasome system, oxidative stress and accelerated inflammatory processes, ranging from neurodegenerative disorder such as Alzheimer's disease Aliev et al, 2003;Aliev, 2002;Arlt et al, 2001;Miyakawa, 2002;Skoog and Gustafson,2002;de La Tore, 2002;Rodin and Thomas, 2001;Zekry et al, 2002;Berliner and Heinecke, 1996;Mayer et al,1991;Layfield et al, 2001;Torzewski et al, 1998;Igarashi et al, 1994;Bulteau et al, 2001;Herrmann et al, 2003) to diabetes mellitus and rheumatoid arthritis (Sevanian and Hochstein, 1985;Halliwell et al, 1986;Onorato et al, 1998;Brod, 2000). This broadly implies, that, appropriate employment of agents to effectively manage rheumatoid arthritis, for instance, may confer some protection against cardiovascular disease and also neurodegenerative pathological conditions, such as Alzheimer's disease and multiple sclerosis, as well (McGeer et al, 1996;Ossandon et al, 2002;Greig et al, 2004; Rheumatoid Arthritis, a Double-faced Syndrome: relevance to neurodegenerative disorder.…”