ubiquinol and Alzheimer-Disease

Structural and functional abnormalities in the cerebral microvasculature have been observed in Alzheimer's disease (AD) patients and animal models. One cause of hypoperfusion is the thickening of the cerebrovascular basement membrane (CVBM) due to increased collagen-IV deposition around capillaries. This study investigated whether these and other alterations in the cerebrovascular system associated with AD can be prevented by long-term dietary supplementation with the antioxidant ubiquinol (Ub) stabilized with Kaneka QH P30 powder containing ascorbic acid (ASC) in a mouse model of advanced AD (3 × Tg-AD mice, 12 months old). Animals were treated from prodromal stages of disease (3 months of age) with standard chow without or with Ub + ASC or ASC-containing vehicle and compared to wild-type (WT) mice. The number of β-amyloid (Aβ) plaques in the hippocampus and entorhinal cortex was higher in female than in male 3 × Tg-AD mice. Extensive regions of hypoxia were characterized by a higher plaque burden in females only. This was abolished by Ub + ASC and, to a lesser extent, by ASC treatment. Irrespective of Aβ burden, increased collagen-IV deposition in the CVBM was observed in both male and female 3 × Tg-AD mice relative to WT animals; this was also abrogated in Ub + ASC- and ASC-treated mice. The chronic inflammation in the hippocampus and oxidative stress in peripheral leukocytes of 3 × Tg-AD mice were likewise reversed by antioxidant treatment. These results provide strong evidence that long-term antioxidant treatment can mitigate plasma oxidative stress, amyloid burden, and hypoxia in the AD brain parenchyma.

Topics: Alzheimer Disease; Animals; Antioxidants; Ascorbic Acid; Cell Hypoxia; Entorhinal Cortex; Female; Hippocampus; Male; Mice; Mice, Inbred C57BL; Plaque, Amyloid; Ubiquinone

Novel multitargeted antioxidants 3-6 were designed by combining the antioxidant features, namely, a benzoquinone fragment and a lipoyl function, of two multifunctional lead candidates. They were then evaluated to determine their profile against Alzheimer's disease. They showed antioxidant activity, improved following enzymatic reduction, in mitochondria and T67 cell line. They also displayed a balanced inhibitory profile against amyloid-beta aggregation and acetylcholinesterase, emerging as promising molecules for neuroprotectant lead discovery.

Topics: Alkanes; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Cell Line, Tumor; Drug Design; Electron Transport; Ethylamines; Humans; Ligands; Protein Binding; Reactive Oxygen Species; Submitochondrial Particles; Thioctic Acid; Ubiquinone

The contribution of mitochondrial dysfunction and oxidative stress to the pathogenesis of Alzheimer's disease (AD) has previously been described. We aimed to investigate whether the balance between the oxidized and reduced forms of coenzyme Q-10 (CoQ-10) is related to the pathogenesis of AD.. Thirty patients with AD (69.0 +/- 4.1 years) and 30 healthy control subjects (63.8 +/- 16.4 years) were enrolled in this study. Concentrations of oxidized CoQ-10 and reduced CoQ-10 were measured by high-performance liquid chromatography using an electrochemical detector.. The percentage of oxidized/total CoQ-10 in the cerebrospinal fluid (%CoQ-10, CSF) was significantly higher in the untreated AD group (78.2 +/- 18.8%) than in the control group (41.3 +/- 10.4%, p < 0.001), and there was a significant negative correlation between %CoQ-10 and the duration of the illness (r(s) = -0.93, p < 0.001).. These findings in living AD patients suggest a possible role for %CoQ-10 in the pathogenesis of the early stage of AD development.

Topics: Aged; Alzheimer Disease; Biomarkers; Chromatography, High Pressure Liquid; Disease Progression; Electron Transport; Female; Humans; Male; Middle Aged; Mitochondrial Diseases; Oxidation-Reduction; Oxidative Stress; Ubiquinone

Diverse oxidative pathways, such as direct oxidation of amino acids, glycoxidation, and lipoxidation could contribute to Alzheimer disease pathogenesis. A global survey for the amount of structurally characterized probes for these reactions is lacking and could overcome the lack of specificity derived from measurement of 2,4-dinitrophenylhydrazine reactive carbonyls. Consequently we analyzed (i) the presence and concentrations of glutamic and aminoadipic semialdehydes, N(epsilon)-(carboxymethyl)-lysine, N(epsilon)-(carboxyethyl)-lysine, and N(epsilon)-(malondialdehyde)-lysine by means of gas chromatography/mass spectrometry, (ii) the biological response through expression of the receptor for advanced glycation end products, (iii) the fatty acid composition in brain samples from Alzheimer disease patients and age-matched controls, and (iv) the targets of N(epsilon)-(malondialdehyde)-lysine formation in brain cortex by proteomic techniques. Alzheimer disease was associated with significant, although heterogeneous, increases in the concentrations of all evaluated markers. Alzheimer disease samples presented increases in expression of the receptor for advanced glycation end products with high molecular heterogeneity. Samples from Alzheimer disease patients also showed content of docosahexaenoic acid, which increased lipid peroxidizability. In accordance, N(epsilon)-(malondialdehyde)-lysine formation targeted important proteins for both glial and neuronal homeostasis such as neurofilament L, alpha-tubulin, glial fibrillary acidic protein, ubiquinol-cytochrome c reductase complex protein I, and the beta chain of ATP synthase. These data support an important role for lipid peroxidation-derived protein modifications in Alzheimer disease pathogenesis.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Blotting, Western; Brain; Carbon; Cerebral Cortex; Databases as Topic; Electrophoresis, Gel, Two-Dimensional; Electrophoresis, Polyacrylamide Gel; Fatty Acids; Fatty Acids, Unsaturated; Female; Glial Fibrillary Acidic Protein; Glycation End Products, Advanced; Glycolysis; Humans; Lipid Metabolism; Lipid Peroxidation; Lysine; Male; Malondialdehyde; NADH Dehydrogenase; Oxygen; Phenylhydrazines; Proteins; Silver Staining; Ubiquinone

Ubiquinol-10 and ubiquinone-10 were measured in plasma of patients with several pathologies known to be associated with increased oxidative stress. Plasma ubiquinol-10, expressed as a percentage of total ubiquinol-10 + ubiquinone-10, was found to be significantly lower in hyperlipidaemic patients and in patients with liver diseases than in age-matched control subjects. In contrast, no decrease in ubiquinol-10 was detected in plasma of patients with coronary heart disease and Alzheimer's disease. Except for ubiquinol-10, no other lipophilic antioxidant was found to be decreased in patients with liver diseases. These data suggest that the level of ubiquinol-10 in human plasma may serve as a marker for liver dysfunction, reflecting its diminished reduction by the liver rather than increased consumption by oxidants.

Topics: Adult; Aged; Alzheimer Disease; Biomarkers; Cholesterol; Coronary Disease; Humans; Hyperlipidemias; Liver Diseases; Middle Aged; Models, Biological; Oxidative Stress; Reference Values; Reproducibility of Results; Triglycerides; Ubiquinone