Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels: implication in the pathogenesis of Alzheimer’s disease. Vasc Health Risk Manag

Department of Biology, University of Texas at San Antonio, San Antonio, Texas 78249-1664, USA.
Vascular Health and Risk Management 02/2008; 4(3):721-30.
Source: PubMed


The pathogenesis that is primarily responsible for Alzheimer's disease (AD) and cerebrovascular accidents (CVA) appears to involve chronic hypoperfusion. We studied the ultrastructural features of vascular lesions and mitochondria in brain vascular wall cells from human AD biopsy samples and two transgenic mouse models of AD, yeast artificial chromosome (YAC) and C57B6/SJL Tg (+), which overexpress human amyloid beta precursor protein (AbetaPP). In situ hybridization using probes for normal and 5 kb deleted human and mouse mitochondrial DNA (mtDNA) was performed along with immunocytochemistry using antibodies against the Abeta peptide processed from AbetaPP, 8-hydroxy-2'-guanosine (8OHG), and cytochrome c oxidase (COX). More amyloid deposition, oxidative stress markers as well as mitochondrial DNA deletions and structural abnormalities were present in the vascular walls of the human AD samples and the AbetaPP-YAC and C57B6/SJL Tg (+) transgenic mice compared to age-matched controls. Ultrastructural damage in perivascular cells highly correlated with endothelial lesions in all samples. Therefore, pharmacological interventions, directed at correcting the chronic hypoperfusion state, may change the natural course of the development of dementing neurodegeneration.

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Article: Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels: implication in the pathogenesis of Alzheimer’s disease. Vasc Health Risk Manag

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    • "We have previously shown that the Rho GTPases, activated by CNF1, are involved in the regulation of mitochondrial functionality in mouse brain [20]. AD and atherosclerosis are characterized by mitochondrial dysfunctions and energy failure that can damage neurons through increased production of reactive oxygen species (ROS), ATP depletion and activation of cell death processes [48], [49]. To verify whether CNF1 can modulate mitochondrial activity, we analyzed ATP levels in the hippocampus (Figure 4A) and frontal cortex (Figure 4B) of apoE4 and apoE3 mice treated with saline or CNF1. "
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    ABSTRACT: Overexpression of pro-inflammatory cytokines and cellular energy failure are associated with neuroinflammatory disorders, such as Alzheimer's disease. Transgenic mice homozygous for human ApoE4 gene, a well known AD and atherosclerosis animal model, show decreased levels of ATP, increased inflammatory cytokines level and accumulation of beta amyloid in the brain. All these findings are considered responsible for triggering cognitive decline. We have demonstrated that a single administration of the bacterial E. coli protein toxin CNF1 to aged apoE4 mice, beside inducing a strong amelioration of both spatial and emotional memory deficits, favored the cell energy restore through an increment of ATP content. This was accompanied by a modulation of cerebral Rho and Rac1 activity. Furthermore, CNF1 decreased the levels of beta amyloid accumulation and interleukin-1β expression in the hippocampus. Altogether, these data suggest that the pharmacological modulation of Rho GTPases by CNF1 can improve memory performances in an animal model of Alzheimer's disease via a control of neuroinflammation and a rescue of systemic energy homeostasis.
    PLoS ONE 06/2013; 8(5):e65898. DOI:10.1371/journal.pone.0065898 · 3.23 Impact Factor
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    • "However, the exact cellular mechanisms behind tumor vascular growth and the relation to NO oxidation products identified as nitrotyrosine formation, lipid peroxidation, ET-1 activity or mtDNA deletion remain to be unknown [2, 54]. Future studies comparing the spectrum of mitochondrial damage and the relationship to NO-dependent oxidative stress-induced damage during the aging process [1, 32, 57] and more importantly, during development and metastasis of tumor are in need of the hour. In addition, it has been also suggested that NO influences cellular differentiation through induction of gene expression [67]. "
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    ABSTRACT: Nitric oxide- (NO-) dependent oxidative stress results in mitochondrial ultrastructural alterations and DNA damage in cases of Alzheimer disease (AD). However, little is known about these pathways in human cancers, especially during the development as well as the progression of primary brain tumors and metastatic colorectal cancer. One of the key features of tumors is the deficiency in tissue energy that accompanies mitochondrial lesions and formation of the hypoxic smaller sized mitochondria with ultrastructural abnormalities. We speculate that mitochondrial involvement may play a significant role in the etiopathogenesis of cancer. Recent studies also demonstrate a potential link between AD and cancer, and anticancer drugs are being explored for the inhibition of AD-like pathology in transgenic mice. Severity of the cancer growth, metastasis, and brain pathology in AD (in animal models that mimic human AD) correlate with the degree of mitochondrial ultrastructural abnormalities. Recent advances in the cell-cycle reentry of the terminally differentiated neuronal cells indicate that NO-dependent mitochondrial abnormal activities and mitotic cell division are not the only important pathogenic factors in pathogenesis of cancer and AD, but open a new window for the development of novel treatment strategies for these devastating diseases.
    Oxidative Medicine and Cellular Longevity 04/2013; 2013(3):962984. DOI:10.1155/2013/962984 · 3.36 Impact Factor
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    • "In the present study, we observed similar decrease in mitochondrial respiratory activity with 30-day reperfusion and 50-min of ischemia induced by 3-VO occlusion see: Table 1 and Fig. (1). The mitochondrial disorders could be defined either, as disorders due to defects of mitochondrial enzymes, or as disorders characterized by morphological abnormalities of mitochondria [2] [22]. Brain is more vulnerable to ROSinduced damage due to its high rate of oxygen consumption, high polyunsaturated lipid content, and relative lack of classic antioxidant enzymes [23] [24]. "
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    ABSTRACT: It is known that oxidative stress and mitochondrial dysfunction both play an important role in animal models of brain ischemia. The present study was undertaken to test whether oral supplementation of coenzyme Q10 (ubiquinone) or creatine citrate could protect against brain ischemia-induced mitochondrial damage in the rats model. Brain ischemia was induced for 50 minutes with three-vessel occlusion (3-VO). Coenzyme Q10 was administered for 30 days before the ischemic event and coenzyme Q10 or creatine citrate for 30 days post-ischemia. Moreover, the concentrations of coenzyme Q10 and α-, γ- tocopherols as well as the formation of thiobarbituric acid reactive substances (TBARS) were measured in brain mitochondria and in plasma. Transient hypoperfusion revealed significant impairment in brain energy metabolism as detected by mitochondrial oxidative phosphorylation as well as decreased concentrations of brain and plasma endogenous antioxidants and increased formation of TBARS in plasma. When compared with the ischemic group, supplementation of coenzyme Q10 was ineffective as a preventive agent. However, the positive effect of therapeutic coenzyme Q10 supplementation was supported by the oxygen consumption values (p < 0.05) and ATP production (p < 0.05) in brain mitochondria, as well as by increased concentration of coenzyme Q9 (p < 0.05) and concentration of α-tocopherol (p < 0.05) in brain mitochondria and by increased concentration of α-tocopherol (p < 0.05) and γ-tocopherol in plasma. This suggests that coenzyme Q10 therapy involves resistance to oxidative stress and improved brain bioenergetics, when supplemented during reperfusion after ischemic brain injury.
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