ubiquinone and Alzheimer-Disease

Coenzyme Q10 (CoQ10) is a component of electron transport chain and acts as an antioxidant. It is also used for preventing neurodegeneration against mitochondrial deficiency and oxidative stress. Therefore, CoQ10 has received increasing attention as therapeutic and preventive intervention for neurodegenerative diseases. This review article focuses mainly on the structure of CoQ10, the function of CoQ10 and the relationship between mitochondrial impairment, oxidative stress and neurodegenerative diseases. In addition, the effects of CoQ10 on Alzheimer's disease, Parkinson's disease, and Huntington's disease are also discussed. Finally, future perspectives regarding development of successful treatment for neurodegenerative diseases are proposed.

Topics: Alzheimer Disease; Humans; Huntington Disease; Neurodegenerative Diseases; Neuroprotection; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Ubiquinone

By the elucidation of high-resolution structures the view of the bioenergetic processes has become more precise. But in the face of these fundamental advances, many problems are still unresolved. We have examined a variety of aspects of energy-transducing membranes from large protein complexes down to the level of protons and functional relevant picosecond protein dynamics. Based on the central role of the ATP synthase for supplying the biological fuel ATP, one main emphasis was put on this protein complex from both chloroplast and mitochondria. In particular the stoichiometry of protons required for the synthesis of one ATP molecule and the supramolecular organisation of ATP synthases were examined. Since formation of supercomplexes also concerns other complexes of the respiratory chain, our work was directed to unravel this kind of organisation, e.g. of the OXPHOS supercomplex I(1)III(2)IV(1), in terms of structure and function. Not only the large protein complexes or supercomplexes work as key players for biological energy conversion, but also small components as quinones which facilitate the transfer of electrons and protons. Therefore, their location in the membrane profile was determined by neutron diffraction. Physico-chemical features of the path of protons from the generators of the electrochemical gradient to the ATP synthase, as well as of their interaction with the membrane surface, could be elucidated by time-resolved absorption spectroscopy in combination with optical pH indicators. Diseases such as Alzheimer's dementia (AD) are triggered by perturbation of membranes and bioenergetics as demonstrated by our neutron scattering studies.

Topics: Adenosine Triphosphate; Alzheimer Disease; Chloroplast Proton-Translocating ATPases; Energy Metabolism; Humans; Light; Membrane Proteins; Mitochondrial Membranes; Models, Biological; Models, Molecular; Multiprotein Complexes; Oxidative Phosphorylation; Protons; Squalene; Ubiquinone

In this work, we review and comment upon the challenges and the 'quo vadis' in Alzheimer's disease drug discovery at the beginning of the new millennium. We emphasize recent approaches that, moving on from a target-centric approach, have produced innovative molecular probes or drug candidates. In particular, the discovery of endosome-targeted BACE1 inhibitors and mitochondria-targeted antioxidants represents a significant advance in Alzheimer's research and therapy. The case study of the development of rasagiline provides an excellent example to support the validity of the multitarget-designed ligand approach to the search for effective medicines for combating Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Drug Delivery Systems; Drug Discovery; Humans; Indans; Organophosphorus Compounds; Ubiquinone

Coenzyme Q10 (CoQ10) is a powerful antioxidant that buffers the potential adverse consequences of free radicals produced during oxidative phosphorylation in the inner mitochondrial membrane. Oxidative stress, resulting in glutathione loss and oxidative DNA and protein damage, has been implicated in many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. Experimental studies in animal models suggest that CoQ10 may protect against neuronal damage that is produced by ischemia, atherosclerosis and toxic injury. Though most have tended to be pilot studies, there are published preliminary clinical trials showing that CoQ10 may offer promise in many brain disorders. For example, a 16-month randomized, placebo-controlled pilot trial in 80 subjects with mild Parkinson's disease found significant benefits for oral CoQ10 1,200 mg/day to slow functional deterioration. However, to date, there are no published clinical trials of CoQ10 in Alzheimer's disease. Available data suggests that oral CoQ10 seems to be relatively safe and tolerated across the range of 300-2,400 mg/day. Randomized controlled trials are warranted to confirm CoQ10's safety and promise as a clinically effective neuroprotectant.

Topics: Alzheimer Disease; Animals; Antioxidants; Brain; Coenzymes; Humans; Huntington Disease; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Parkinson Disease; Randomized Controlled Trials as Topic; Ubiquinone; Vitamins

MitoQ is an orally active antioxidant that has the ability to target mitochondrial dysfunction. The agent is currently under development by Antipodean Pharmaceuticals Inc in phase II clinical trials for Parkinson's disease and liver damage associated with HCV infection. MitoQ has demonstrated encouraging preclinical results in numerous studies in isolated mitochondria, cells and tissues undergoing oxidative stress and apoptotic death. MitoQ aims to not only mimic the role of the endogenous mitochondrial antioxidant coenzyme Q10 (CoQ10), but also to augment substantially the antioxidant capacity of CoQ to supraphysiological levels in a mitochondrial membrane potential-dependent manner. MitoQ represents the first foray into the clinic in an attempt to deliver an antioxidant to an intracellular region that is responsible for the formation of increased levels of potentially deleterious reactive oxygen species. Results from the clinical trials with MitoQ will have important repercussions on the relevance of a mitochondrial-targeted approach.

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Antiparkinson Agents; Apoptosis; Clinical Trials as Topic; Friedreich Ataxia; Hepatitis C; Humans; Mitochondria; Myocardial Reperfusion Injury; Neuroprotective Agents; Organophosphorus Compounds; Oxidative Stress; Parkinson Disease; Ubiquinone

There is substantial evidence that mitochondrial dysfunction and oxidative damage may play a key role in the pathogenesis of neurodegenerative disease. Evidence supporting this in both Alzheimer's and Parkinson's diseases is continuing to accumulate. This review discusses the increasing evidence for a role of both mitochondrial dysfunction and oxidative damage in contributing to beta-amyloid deposition in Alzheimer's disease. I also discuss the increasing evidence that Parkinson's disease is associated with abnormalities in the electron transport gene as well as oxidative damage. Lastly, I reviewed the potential efficacy of coenzyme Q as well as a number of other antioxidants in the treatment of both Parkinson's and Alzheimer's diseases.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Coenzymes; Humans; Mitochondria; Mitochondrial Diseases; Neurons; Neuroprotective Agents; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Reactive Oxygen Species; Ubiquinone

Ubiquitinated inclusions and selective neuronal cell death are considered the pathological hallmarks of Parkinson's disease and other neurodegenerative diseases. Recent genetic, pathological and biochemical evidence suggests that dysfunction of ubiquitin-dependent protein degradation by the proteasome might be a contributing, if not initiating factor in the pathogenesis of these diseases. In neuronal cell culture models inhibition of the proteasome leads to cell death and formation of fibrillar ubiquitin and alpha-synuclein-positive inclusions, thus modeling some aspects of Lewy body diseases. The processes of inclusion formation and neuronal cell death share some common mechanisms, but can also be dissociated at a certain level.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Cell Death; Humans; Inclusion Bodies; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurons; Parkinson Disease; Synucleins; Ubiquinone

Topics: Alzheimer Disease; Animals; Antioxidants; Benzoquinones; Cerebrovascular Disorders; Friedreich Ataxia; Humans; Liver Diseases; Ubiquinone

Alzheimer's disease is one of the most challenging brain disorders and has profound medical and social consequences. It affects approximately 15 million persons worldwide, and many more family members and care givers are touched by the disease. The initiating molecular event(s) is not known, and its pathophysiology is highly complex. However, free radical injury appears to be a fundamental process contributing to the neuronal death seen in the disorder, and this hypothesis is supported by many (although not all) studies using surrogate markers of oxidative damage. In vitro and animal studies suggest that various compounds with antioxidant ability can attenuate the oxidative stress induced by beta-amyloid. Recently, clinical trials have demonstrated potential benefits from treatment with the antioxidants, vitamin E, selegiline, extract of Gingko biloba, and idebenone. Further studies are warranted to confirm these findings and explore the optimum timing and antioxidant combination of such treatments in this therapeutically frustrating disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Antioxidants; Ascorbic Acid; Benzoquinones; Central Nervous System; Central Nervous System Diseases; Clinical Trials as Topic; Drug Therapy, Combination; Free Radicals; Ginkgo biloba; Humans; Lipid Peroxidation; Neuroprotective Agents; Oxidation-Reduction; Phytotherapy; Plants, Medicinal; Selegiline; Ubiquinone; Vitamin E

The degeneration of cholinergic neurons may be responsible for cognitive impairment in patients with Alzheimer's disease (AD). Since nerve growth factor (NGF) plays an important role in the survival and maintenance of cholinergic neurons in the central nervous system, this factor may have some beneficial effects on the cognitive impairment observed in patients with AD. However, since NGF does not cross the blood-brain barrier and is easily metabolized when administered peripherally, it can only be used when directly injected into the brain. In this review, we show that repeated oral administration of the NGF synthesis stimulators, idebenone and propentofylline, partially restored the age-associated decrease of NGF in the frontal and parietal cortices. Furthermore, this treatment attenuated the impairment of performance in the water maze, passive avoidance, and habituation tasks in rats with bilateral forebrain lesions, and in rats which had received continuous infusion of anti-NGF antibody into the septum. The behavioral improvement induced by idebenone and propentofylline was accompanied by recovery of both the reduced activity of choline acetyltransferase and the changes in [3H]QNB binding. These results suggest that the use of NGF synthesis stimulators may provide a novel therapeutic approach to cholinergic dysfunction.

Topics: Alzheimer Disease; Animals; Benzoquinones; Humans; Nerve Growth Factors; Nootropic Agents; Rats; Ubiquinone; Xanthines

The evaluation of the short-term effect of topically applied coenzyme Q10 (CoQ10) on retina and choroid in Alzheimer's disease (AD) was aimed in this study.. Randomized controlled study included a total of 93 patients, 62 of whom with AD. Thirty (32.3%) AD patients received treatment (Group 1), 32 (34.4%) AD patients observed without treatment (Group 2), and Group 3 included 31 (33.3%) healthy controls (HC). Neurological and ophthalmological examinations including optical coherence tomography (OCT) were executed.. Retinal nerve fiber layer (RNFL) thickness in all quadrants increased following CoQ10 treatment in Group 1; however significant rise yielded in average and temporal quadrant RNFL thickness. Average and superonasal sector ganglion cell-inner plexiform layer (GCIPL) thickness increased significantly following CoQ10 treatment. The correlation analysis between difference in pre- and posttreatment OCT values in Group 1 revealed that rise in average RNFL thickness was inversely correlated with duration of the disease and rise in average GCIPL thickness and superonasal sector thickness was inversely correlated with severity of the disease.. Short-term topical CoQ10 resulted in improvement in AD related retinal ganglion cell (RGC) loss which may reflect the salvage of some RGCs in the reversible transitional phase. More bioavailability through intravitreal route of administration and longer duration of effect with sustained release forms may possibly help enhalting the RGC loss, especially incipience of neurodegenerative diseases.

Topics: Aged; Alzheimer Disease; Choroid; Dose-Response Relationship, Drug; Female; Humans; Male; Ophthalmic Solutions; Retinal Diseases; Retinal Ganglion Cells; Salvage Therapy; Tomography, Optical Coherence; Ubiquinone; Vitamins

To evaluate whether antioxidant supplements presumed to target specific cellular compartments affected cerebrospinal fluid (CSF) biomarkers.. Double-blind, placebo-controlled clinical trial.. Academic medical centers.. Subjects with mild to moderate Alzheimer disease.. Random assignment to treatment for 16 weeks with 800 IU/d of vitamin E (α-tocopherol) plus 500 mg/d of vitamin C plus 900 mg/d of α-lipoic acid (E/C/ALA); 400 mg of coenzyme Q 3 times/d; or placebo.. Changes from baseline to 16 weeks in CSF biomarkers related to Alzheimer disease and oxidative stress, cognition (Mini-Mental State Examination), and function (Alzheimer's Disease Cooperative Study Activities of Daily Living Scale).. Seventy-eight subjects were randomized; 66 provided serial CSF specimens adequate for biochemical analyses. Study drugs were well tolerated, but accelerated decline in Mini-Mental State Examination scores occurred in the E/C/ALA group, a potential safety concern. Changes in CSF Aβ42, tau, and P-tau(181) levels did not differ between the 3 groups. Cerebrospinal fluid F2-isoprostane levels, an oxidative stress biomarker, decreased on average by 19% from baseline to week 16 in the E/C/ALA group but were unchanged in the other groups.. Antioxidants did not influence CSF biomarkers related to amyloid or tau pathology. Lowering of CSF F2-isoprostane levels in the E/C/ALA group suggests reduction of oxidative stress in the brain. However, this treatment raised the caution of faster cognitive decline, which would need careful assessment if longer-term clinical trials are conducted.. clinicaltrials.gov Identifier: NCT00117403.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; alpha-Tocopherol; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Ascorbic Acid; Biomarkers; Cholinesterase Inhibitors; Dietary Supplements; Double-Blind Method; F2-Isoprostanes; Female; Follow-Up Studies; Humans; Male; Memantine; Mental Status Schedule; Middle Aged; Peptide Fragments; Retrospective Studies; tau Proteins; Thioctic Acid; Ubiquinone

To determine the effect of idebenone on the rate of decline in Alzheimer's disease (AD).. A 1-year, multicenter, double-blind, placebo-controlled, randomized trial was conducted. Subjects were over age 50 with a diagnosis of probable AD and had Mini-Mental State Examination (MMSE) scores between 12 and 25. Subjects were treated with idebenone 120, 240, or 360 mg tid, each of which was compared with placebo. Primary outcome measures were the Alzheimer's Disease Assessment Scale-Cognitive Subcomponent (ADAS-Cog) and a Clinical Global Impression of Change (CGIC). Secondary outcome measures included measurements of activities of daily living, the Behavioral Pathology in Alzheimer's Disease Rating Scale, and the MMSE.. Five hundred thirty-six subjects were enrolled and randomized to the four groups. Except for a slight difference in age, there were no differences in patient characteristics at baseline. For the primary outcome measures, there were no significant overall differences between the treatment groups in the prespecified four-group design. In an exploratory two-group analysis comparing all three treated groups combined with placebo, drug-treated patients performed better on the ADAS-Cog in both the intent-to-treat (ITT) and completers analyses. There were no differences in the CGIC scores for the ITT or completers analyses in either the four-group or the two-group analyses. There were no overall differences on any of the secondary outcome measures in any of the analyses.. Idebenone failed to slow cognitive decline in AD that was of sufficient magnitude to be clinically significant.

Topics: Aged; Alzheimer Disease; Benzoquinones; Cognition Disorders; Disease Progression; Double-Blind Method; Female; Humans; Male; Middle Aged; Treatment Failure; Ubiquinone

This study evaluated the safety and efficacy of idebenone vs. tacrine in a prospective, randomized, double-blind, parallel-group multicenter study in patients suffering from dementia of the Alzheimer type (DAT) of mild to moderate degree. Diagnosis was based on DSM-III-R (primary degenerative dementia) and NINCDS-ADRDA criteria (probable Alzheimer's disease). A total of 203 patients of both sexes aged between 40 and 90 years were randomized to either idebenone 360 mg/day (n = 104) or tacrine up to 160 mg/day (n = 99) and treated for 60 weeks. The primary outcome measure was the Efficacy Index Score (EIS). The EIS combines dropout as well as the relevant improvements individually across the three levels of assessment (cognitive function, activities of daily living, global function). Secondary outcome measures were the ADAS-Cog score, the NOSGER-IADL score and the clinical global response (CGI-Improvement). After 60 weeks of treatment, 28.8 % of the patients randomized to idebenone, but only 9.1 % of the patients randomized to tacrine were still on the drug. In the LOCF analysis, 50 % of the patients randomized to idebenone but only 39.4 % of the patients randomized to tacrine showed an improvement in the Efficacy Index Score or at least one of the secondary outcome variables. The primary efficacy measurement was the change of the Efficacy Index Score from baseline to the assessment after 60 weeks treatment. The analysis was done on intention-to-treat (ITT) in a before-and-after test design. Patients randomized to idebenone showed a higher benefit from treatment than patients randomized to tacrine. We conclude that the benefit-risk ratio is favorable for idebenone compared to tacrine, and furthermore, that this ratio is likely to be similar when comparing idebenone to other cholinesterase inhibitors.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Antioxidants; Benzoquinones; Double-Blind Method; Female; Humans; Male; Middle Aged; Nootropic Agents; Tacrine; Treatment Outcome; Ubiquinone

The 2-year efficacy and safety of idebenone were studied in a prospective, randomized, double-blind multicentre study in 3 parallel groups of patients with dementia of the Alzheimer type (DAT) of mild to moderate degree. A total of 450 patients were randomized to either placebo for 12 months, followed by idebenone 90 mg tid for another 12 months (n = 153) or idebenone 90 mg tid for 24 months (n = 148) or 120 mg tid for 24 months (n = 149). The primary outcome measure was the total score of the Alzheimer's Disease Assessment Scale (ADAS-Total) at month 6. Secondary outcome measures were the ADAS cognitive (ADAS-Cog) and noncognitive score (ADAS-Noncog), the clinical global response (CGI-Improvement), the SKT neuropsychological test battery, and the Nurses' Observation Scale for Geriatric Patients (NOSGER-Total and IADL subscale). Safety parameters were adverse events, vital signs, ECG and clinical laboratory parameters. During the placebo controlled period (the first year of treatment), idebenone showed statistically significant dose-dependent improvement in the primary efficacy variable ADAS-Total and in all the secondary efficacy variables. There was no evidence for a loss of efficacy during the second year of treatment, as a further improvement of most efficacy variables was found in the second year in comparison to the results at the 12 months visit. Also, a clear dose effect relationship (placebo/90 mg < idebenone 90 mg < idebenone 120 mg) was maintained throughout the second year of treatment. This suggests that idebenone exerts its beneficial therapeutic effects on the course of the disease by slowing down its progression. Safety and tolerability of idebenone were good and similar to placebo during the first year of treatment and did not change during the second year.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Antioxidants; Benzoquinones; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prospective Studies; Psychiatric Status Rating Scales; Time Factors; Ubiquinone

Two doses of idebenone were studied in a prospective, randomized, double-blind, placebo-controlled multicentre study in patients suffering from dementia of the Alzheimer type (DAT) of mild to moderate degree. Diagnosis was based on DSM-III-R (primary degenerative dementia) and NINCDS-ADRDA criteria (probable Alzheimer's disease). A total of 300 patients were randomized to either placebo, idebenone 30 mg t.i.d. or 90 mg t.i.d. (n = 100, each) and treated for 6 months. The primary outcome measure was the total score of the Alzheimer's Disease Assessment Scale (ADAS-Total) at month 6. Secondary outcome measures were the ADAS cognitive (ADAS-Cog) and noncognitive scores (ADAS-Noncog), the clinical global response (CGI-Improvement), the MMSE, the Digit Symbol Substitution test (DSS) and several scales for the assessment of daily activities (the self- and observer-rating scales NAA and NAB of the Nuremberg Age Inventory NAI and Greene's Assessment). Safety parameters were adverse events, vital signs, ECG and clinical laboratory parameters. Clinical and psychometric evaluations were performed at baseline, and after 1, 3 and 6 months of treatment. After month 6 idebenone 90 mg t.i.d. showed statistically significant improvement in the primary efficacy variable ADAS-Total and in ADAS-Cog. An analysis of therapy responders performed for 3 outcome measures (CGI-global improvement, ADAS-Cog, ADAS-Noncog), selected to represent different domains of assessment, revealed significant superiority of idebenone 90 mg t.i.d. with respect to placebo in each of the 3 variables and in the concordance of responses across the 3 measures. Exploratory results for a subgroup of patients (ADAS-Total > or = 20) showed dose-related superiority of idebenone additionally on ADAS-Noncog and the CGI-Improvement scale. Safety results were inconspicuous for all assessments. The study results demonstrate the efficacy and safety of idebenone in the treatment of DAT patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Benzoquinones; Cognition; Double-Blind Method; Female; Humans; Male; Middle Aged; Treatment Outcome; Ubiquinone

Alzheimer's disease (AD) is a degenerative disease that causes memory and learning impairments as well as dementia. Coenzyme Q10 (CoQ10) is an anti-inflammatory and anti-oxidative stress supplement that can improve inflammation and oxidative stress associated with AD. This study investigated the effects of drug delivery of COQ10 by exosomes derived from adipose-derived stem cells (ADSCs-Exo) on cognition, memory, and neuronal proliferation in a rat model of Streptozotocin (STZ)-induced AD. Since the establishment of the AD model, the rats have received intraperitoneal injections of CoQ10, Exo, or CoQ10-loaded ADSCs-Exo (Exo+ CoQ10). The passive avoidance test and the Morris water maze (MWM) were used to assess memory and cognition changes. Cell density was determined using histological methods. The expression of BDNF was measured using an ELISA kit. SOX2 expression was determined using immunohistochemistry. According to the results of the MWM and passive avoidance task, Exo+CoQ10 significantly improved STZ-induced memory impairment compared to CoQ10 and Exo groups alone. Furthermore, BDNF expression increased in the STZ-induced rats after Exo+ CoQ10, when compared to the CoQ10 and Exo groups. In addition, Exo+CoQ10 had the highest cell density and SOX2 gene expression, when compared to the CoQ10 and Exo groups. According to the findings of this study, Exo+ COQ10 enhanced cognition and memory deficiency in Alzheimer's disease by boosting BDNF and SOX2 levels in the hippocampus. Hence, the use of exosomes derived from adipose-derived stem cells as the carrier of CoQ10 may increase the therapeutic effect of CoQ10, which can possibly be due to the regenerative properties of the exosomes.

Topics: Alzheimer Disease; Animals; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Exosomes; Neuroprotective Agents; Rats; Stem Cells; Streptozocin; Ubiquinone

Idebenone (IDB) has demonstrated the potential to treat mitochondrial and neurodegenerative diseases, including Alzheimer's disease (AD). However, its therapeutic effects are compromised by poor compliance due to low bioavailability. The objective of this study is to fabricate IDB nanorods (IDBNRs) to improve oral bioavailability and increase concentrations in the brain in order to enhance therapeutic effects of IDB in the treatment of AD. IDBNRs showed desired sizes and rod-shaped morphologies. The release rate and the antioxidant activity of IDBNRs were improved relative to other delivery routes. The plasma and brain concentrations were enhanced due to rapid release into the systemic circulation. In behavioral tests, mice treated orally with IDBNRs showed amelioration of AD-induced impairment of learning and memory. Thus, because of improved efficiency of drug delivery, doses can be reduced, and the compliance and therapeutic experience of patients can be improved. IDBNRs may provide effective and convenient treatments for AD patients in the future.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Nanotubes; Neuroprotective Agents; Ubiquinone

Coenzyme Q10 (CoQ10) supplementation can improve cognition in patients with Alzheimer's disease (AD) and AD transgenic model mice. To ameliorate the discomfort that patients with AD suffer after several blood extractions, a non-invasive method for detecting urine CoQ10 levels needs to be established.. Here, we developed a new technique of fluorescence spectrophotometry with ethyl cyanoacetate (FS-ECA), on the basis of the principle that the chemical derivative obtained from the interaction between CoQ10 and ECA was detected by a fluorescence detector at λ. The limits of detection (LOD) and limits of quantization (LOQ) (serum: 0.021 and 0.043 mg/L; urine: 0.012 and 0.025 mg/L) determined by the FS-ECA method were similar to that obtained through HPLC-UV (serum: 0.017 and 0.035 mg/L; urine: 0.012 and 0.025 mg/L). More importantly, this new FS-ECA technique as well as the conventional HPLC-UV method could detect a marked difference in urine CoQ10 levels between AD and controls.. Our findings suggest that this non-invasive method for quantifying urine CoQ10 potentially replaces HPLC to detect blood CoQ10.

Topics: Acetates; Aged; Alzheimer Disease; Chemistry, Clinical; Chromatography, High Pressure Liquid; Fluorescence; Humans; Limit of Detection; Spectrometry, Fluorescence; Temperature; Time Factors; Ubiquinone

Alzheimer's disease (AD) is the most common form of dementia that progressively disrupts neurocognitive function, which has neither cure nor effective treatment. Hypercholesterolemia might be involved in brain alterations that could evolve into AD. The present study aims to evaluate the potential of omega-3, Co-enzyme Q10 (Co-Q10), as well as their combination in ameliorating hypercholesterolemia-initiated AD-like disease. We adapted a hypercholesterolemic (HC) rat model, a model of oxidative stress-mediated neurodegeneration, to study AD-like pathology. Hypercholesterolemia resulted in increased lipid peroxidation coupled with declined nitric oxide production, reduced glutathione levels, and decreased antioxidant activities of glutathione-s-transferase (GST) and glutathione peroxidase (GSH-Px) in the brain. Moreover, hypercholesterolemia resulted in decreased acetylcholine (ACh) levels and increased acetylcholine-esterase (AChE) activity, along with an increment of tumor necrosis factor and amyloid-β 42. Behaviorally, HC-rats demonstrated depressive-like behavior and declined memory. Treatment of HC-rats with omega-3 and Co-Q10 (alone or in combination) alleviated the brain oxidative stress and inflammation, regulated cholinergic functioning, and enhanced the functional outcome. These findings were verified by the histopathological investigation of brain tissues. This neuroprotective potential of omega-3 and Co-Q10 was achieved through anti-oxidative, anti-inflammatory, anti-amyloidogenic, pro-cholinergic, and memory-enhancing activities against HC-induced AD-like disease; suggesting that they may be useful as prophylactic and therapeutic agents against the neurotoxic effects of hypercholesterolemia.

Topics: Alzheimer Disease; Animals; Brain; Drug Therapy, Combination; Fatty Acids, Omega-3; Hypercholesterolemia; Male; Maze Learning; Neuroprotective Agents; Random Allocation; Rats; Rats, Wistar; Ubiquinone

Oxidative stress, likely stemming from dysfunctional mitochondria, occurs before major cognitive deficits and neuropathologies become apparent in Alzheimer's disease (AD) patients and in mouse models of the disease. We previously reported that treating 2- to 7-month-old 3xTg-AD mice with the mitochondria-targeted antioxidant MitoQ (mitoquinone mesylate: [10-(4,5-Dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl](triphenyl)phosphonium methanesulfonate), a period when AD-like pathologies first manifest in them, prevents AD-like symptoms from developing. To elucidate further a role for mitochondria-derived oxidative stress in AD progression, we examined the ability of MitoQ to inhibit AD-like pathologies in these mice at an age in which cognitive and neuropathological symptoms have fully developed. 3xTg-AD female mice received MitoQ in their drinking water for five months beginning at twelve months after birth. Untreated 18-month-old 3xTg-AD mice exhibited significant learning deficits and extensive AD-like neuropathologies. MitoQ-treated mice showed improved memory retention compared to untreated 3xTg-AD mice as well as reduced brain oxidative stress, synapse loss, astrogliosis, microglial cell proliferation, Aβ accumulation, caspase activation, and tau hyperphosphorylation. Additionally, MitoQ treatment significantly increased the abbreviated lifespan of the 3xTg-AD mice. These findings support a role for the involvement of mitochondria-derived oxidative stress in the etiology of AD and suggest that mitochondria-targeted antioxidants may lessen symptoms in AD patients.

Topics: Alzheimer Disease; Animals; Antioxidants; Apoptosis; Brain; Female; Gliosis; Longevity; Male; Memory; Mice; Mice, Inbred C57BL; Mitochondria; Organophosphorus Compounds; Oxidative Stress; Ubiquinone

Alzheimer's disease (AD) is the most prevalent form of dementia and is associated with loss of memory, amyloid-beta plaque buildup, and neurofibrillary tangles. These features might be a result of neuronal cell death in the cerebral cortex and hippocampal regions of the brain. AD pathologies can be attributed to a variety of biochemical consequences including mitochondrial dysfunction, increased oxidative stress, and autophagy inhibition. Unfortunately, current therapeutics are limited only to symptomatic relief and do not halt the progression of neurodegeneration. Previous in vitro experiments have shown that a water-soluble formulation of coenzyme-Q

Topics: Alzheimer Disease; Animals; Autophagy; Beclin-1; Cell Death; Cellular Senescence; Cerebral Cortex; Disease Models, Animal; Fibroblasts; Humans; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase 8; Mutation; Neuroprotection; Presenilin-1; Ubiquinone; Up-Regulation

Oxidative stress plays a key role in contributing to β-amyloid (Aβ) deposition in Alzheimer's disease (AD). Coenzyme Q10 (Q10) is a powerful antioxidant that buffers the potential adverse consequences of free radicals. In this study, we investigated the neuroprotective effects of Q10 on Aβ-induced impairment in hippocampal long-term potentiation (LTP), a widely researched model of synaptic plasticity, which occurs during learning and memory, in a rat model of AD. In this study, 50 adult male Wistar rats were assigned to five groups: control group (saline); sham group; intraventricular PBS injection, Aβ group; intraventricular Aβ injection, Q10 group; and Q10 via oral gavage and Q10 + Aβ group. Q10 was administered via oral gavage, once a day, for 3 weeks before and 3 weeks after the Aβ injection. After the treatment period, in vivo electrophysiological recordings were performed to quantify the excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude in the hippocampal dentate gyrus. LTP was created by a high-frequency stimulation of the perforant pathway. Following LTP induction, the EPSP slope and PS amplitude were significantly diminished in Aβ-injected rats, compared with sham and control rats. Q10 treatment of Aβ-injected rats significantly attenuated these decreases, suggesting that Q10 reduces the effects of Aβ on LTP. Aβ significantly increased serum malondialdehyde levels and total oxidant levels, whereas Q10 supplementation significantly reversed these parameters and increased total antioxidant capacity levels. The present findings suggested that Q10 treatment offers neuroprotection against the detrimental effects of Aβ on hippocampal synaptic plasticity via its antioxidant activity.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Dentate Gyrus; Disease Models, Animal; Excitatory Postsynaptic Potentials; Hippocampus; Long-Term Potentiation; Male; Memory; Memory Disorders; Neuronal Plasticity; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Rats; Rats, Wistar; Synaptic Transmission; Temporal Lobe; Ubiquinone

Alzheimer's disease is a neurodegenerative disorder characterized by a progressive decline of cognitive abilities as well as bone loss. Physical and mental activities maintain cognitive functions as well as increase bone mass by inhibiting bone resorption. VIN and CoQ10 are neuroprotective drugs that possess anti-inflammatory and antioxidant properties.. To study the effect of PH&M on enhancing the neuroprotective role of VIN and CoQ10 combination during induction of AD model in rats besides their role against bone mass loss associated with AD model.. Six groups of rats were received saline, AlCl. VIN and CoQ10 combination together with PH&M significantly attenuated the neurodegeneration induced by AlCl. Neuroprotective drugs together with PH&M have a more protective effect against AD and bone loss rather than PH&M alone.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Bone Remodeling; Brain; Cognition; Combined Modality Therapy; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Swimming; Ubiquinone; Vinca Alkaloids; Vitamins

 Alzheimer's disease (AD) is one of the most common neurodegenerative pathologies for which there are no effective therapies to halt disease progression. Given the increase in the incidence of this disorder, there is an urgent need for pharmacological intervention. Unfortunately, recent clinical trials produced disappointing results. Molecular mechanisms of AD are converging on the notion that mitochondrial dysfunction, oxidative stress, and accumulation of dysfunctional proteins are involved in AD pathology. Previously, we have shown that a water-soluble formulation of Coenzyme Q10 (Ubisol-Q10), an integral part of the electron transport chain, stabilizes mitochondria and prevents neuronal cell death caused by neurotoxins or oxidative stress both in vitro and in vivo. In this study, we evaluated the neuroprotective effects of Ubisol-Q10 treatment in double transgenic AD mice. In the present study, we report that providing Ubisol-Q10 in drinking water (at a dose of ∼6 mg/kg/day) reduced circulating amyloid-β (Aβ) peptide, improved long term memory, preserved working spatial memory, and drastically inhibited Aβ plaque formation in 18-month-old transgenic mice compared to an untreated transgenic group. Thus Ubisol-Q10 supplementation has the potential to inhibit the progression of neurodegeneration, leading to a better quality of life for humans suffering with AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Male; Maze Learning; Memory; Memory Disorders; Mice; Mice, Transgenic; Microglia; Mutation; Nerve Tissue Proteins; Peptide Fragments; Presenilin-1; Ubiquinone; Vitamins

Our laboratories have demonstrated that accumulation of oligomeric amyloid β (OAβ) in neurons is an essential step leading to OAβ-mediated mitochondrial dysfunction.. Alzheimer's disease (AD) and matching control hippocampal neurons, astrocytes, and microglia were isolated by laser-captured microdissection from the same subjects, followed by whole-transcriptome sequencing. Complementary in vitro work was performed in OAβ-treated differentiated SH-SY5Y, followed by the use of a novel CoQ. We report decreases in the same mitochondrial-encoded mRNAs in Alzheimer's disease laser-captured CA1 neurons and in OAβ-treated SH-SY5Y cells, but not in laser-captured microglia and astrocytes. Pretreatment with a novel CoQ. Similarity of expression changes in neurons from Alzheimer's disease brain and neuronal cells treated with OAβ, and the effect of a CoQ

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Astrocytes; Cell Line, Tumor; Female; Hippocampus; Humans; In Vitro Techniques; Laser Capture Microdissection; Male; Microglia; Microscopy, Electron, Transmission; Neurons; RNA, Messenger; RNA, Mitochondrial; Ubiquinone

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

Inflammation plays critical roles in the pathogenic mechanisms of several neurodegenerative disorders including Alzheimer's disease (AD). Previous study revealed that CoQ10 augmented cellular antioxidant defense capacity, thereby protecting PC12 cells from oxidative neurotoxicity. However, the mechanism by which CoQ10 inhibits inflammation remains unknown. In this study, we aim to examine the effects of CoQ10 on Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Apoptosis; Cell Survival; Inflammation; Neuroprotective Agents; NF-kappa B; NF-KappaB Inhibitor alpha; PC12 Cells; Peptide Fragments; Rats; Signal Transduction; Ubiquinone

The molecular mechanisms underlying cognitive impairment in Alzheimer's disease (AD) remain largely unclear. In the present study, we were aimed to identify the potential key molecules involved in spatial memory impairment in a triple transgenic (3xTg-AD) mouse model of AD. By employing two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry, we revealed a total of 24 differentially expressed proteins in hippocampus of 9-month-old 3xTg-AD mice with significant spatial memory impairment in comparison to the age-matched controls. These differentially expressed proteins can be categorized into several functional classifications that are related to synaptic/memory-, energy metabolism-, intracellular transport-, cell cycle-, cellular defense and structure, and stress response. To further verify the target proteins that may underlie the memory deficits, we pre-treated the 3xTg-AD mice for 3 months with coenzyme Q10 (CoQ10) (800 mg/kg body weight/day), a powerful endogenous antioxidant that has been shown to be able to prevent memory deficits in several AD mouse models. We found that administration of CoQ10 altered the expression levels of nine proteins in hippocampus of 3xTg-AD mice with simultaneous improvement of spatial memory. Interestingly, complexin-1/2, two molecules which were shown to alter LTP, were modulated (i.e., the levels were reduced in 3xTg-AD mice and CoQ10 restored the levels) in response to CoQ10 treatment among these nine proteins. Furthermore, we found that adeno-associated virus serotype 9 (AAV-9)-mediated overexpression of complexin-1/2 prevented memory impairment in the AD mouse model. Taken together, this study has identified a number of differentially expressed proteins in hippocampus of 3xTg-AD mice and the control in presence or absence of CoQ10. The modulation of complexin-1/2 expression by CoQ10 may contribute to the amelioration of memory impairment in the AD transgenic mice.

Topics: Alzheimer Disease; Animals; Blotting, Western; Dependovirus; Electrophoresis, Gel, Two-Dimensional; Gene Ontology; Hippocampus; Humans; Memory Disorders; Mice, Transgenic; Protein Interaction Maps; Proteomics; Reproducibility of Results; Spatial Memory; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tandem Mass Spectrometry; Ubiquinone

Topics: Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Berberine; Humans; Inflammation; Metabolic Diseases; Selenium; Small Molecule Libraries; Ubiquinone; Vanadium Compounds

Mitochondrial dysfunctions significantly contribute to the pathogenesis of Alzheimer's disease (AD). Here, we studied the relationship between AD and changes in the mitochondrial rates of respiration in blood platelets, respiratory chain complexes activity, and coenzyme Q10 plasma concentrations. In intact platelets obtained from AD patients, we observed a decrease in endogenous basal respiration rates, a decrease in the maximal capacity of the electron transport system (ETS), and higher respiratory rates after inhibiting complex I of the ETS. When normalized for citrate synthase activity, rotenone inhibited respiratory rates and complex I activity was significantly altered. In permeabilized platelets, mitochondrial respiration was completely rescued by the addition of complex I substrates. The changes in mitochondrial respiratory parameters were not associated with the progression of AD except for the capacity of the ETS in permeabilized platelets. In AD, complex I activity was increased, complex IV activity was decreased, and coenzyme Q10 plasma concentrations were decreased. Our data indicate that both insufficiency in substrates entering into the oxidative phosphorylation system and functional disturbances in the ETS complex are responsible for the decrease in respiration observed in intact platelets in AD patients. Analyses of complex IV activity, the respiratory rates of intact platelets, and the capacity of the ETS in permeabilized platelets may enable the characterization of mitochondrial dysfunctions in the initial stage of AD.

Topics: Aged; Alzheimer Disease; Apolipoproteins E; Biomarkers; Blood Platelets; Citrate (si)-Synthase; Electron Transport Complex I; Electron Transport Complex IV; Female; Gene Frequency; Humans; Male; Mental Status Schedule; Middle Aged; Mitochondria; Polymorphism, Genetic; ROC Curve; Ubiquinone

Alzheimer's disease (AD) is the most common form of dementia. The deposition of brain amyloid-β peptides (Aβ), which are cleaved from amyloid precursor protein (APP), is one of the pathological hallmarks of AD. Aβ-induced oxidative stress and neuroinflammation play important roles in the pathogenesis of AD. Antroquinonol, a ubiquinone derivative isolated from Antrodia camphorata, has been shown to reduce oxidative stress and inflammatory cytokines via activating the nuclear transcription factor erythroid-2-related factor 2 (Nrf2) pathway, which is downregulated in AD. Therefore, we examined whether antroquinonol could improve AD-like pathological and behavioral deficits in the APP transgenic mouse model. We found that antroquinonol was able to cross the blood-brain barrier and had no adverse effects via oral intake. Two months of antroquinonol consumption improved learning and memory in the Morris water maze test, reduced hippocampal Aβ levels, and reduced the degree of astrogliosis. These effects may be mediated through the increase of Nrf2 and the decrease of histone deacetylase 2 (HDAC2) levels. These findings suggest that antroquinonol could have beneficial effects on AD-like deficits in APP transgenic mouse.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Behavior, Animal; Blood-Brain Barrier; Disease Models, Animal; Hippocampus; Histone Deacetylase 2; Mice; Mice, Transgenic; NF-E2-Related Factor 2; Rats; Spatial Learning; Spatial Memory; Ubiquinone

Alzheimer's disease (AD) is the most common fatal neurodegenerative disease affecting the elderly worldwide. There is an urgent need to identify novel biomarkers of early AD. This study aims to search for potential early protein biomarkers in serum from a triple transgenic (PS1M146V/APPSwe/TauP301L) mouse model. Proteomic analysis via two-dimensional fluorescence difference gel electrophoresis was performed on serum samples from wild-type (WT) and triple transgenic mice that were treated with or without coenzyme Q10 (CoQ10) (800 mg/kg body weight/day), a powerful endogenous antioxidant displaying therapeutic benefits against AD pathology and cognitive impairment in multiple AD mouse models, for a period of three months beginning at two months of age. A total of 15 differentially expressed serum proteins were identified between the WT and AD transgenic mice. The administration of CoQ10 was found to alter the changes in the differentially expressed serum proteins by upregulating 10 proteins and down-regulating 10 proteins. Among the proteins modulated by CoQ10, clusterin and α-2-macroglobulin were validated via ELISA assay. These findings revealed significant changes in serum proteins in the AD mouse model at an early pathological stage and demonstrated that administration of CoQ10 could modulate these changes in serum proteins. Our study suggested that these differentially expressed serum proteins could serve as potential protein biomarkers of early AD and that screening for potential candidate AD therapeutic drugs and monitoring of therapeutic effects could be performed via measurement of the changes in these differentially expressed serum proteins.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Antioxidants; Blood Proteins; Databases, Protein; Disease Models, Animal; Electrophoresis, Gel, Two-Dimensional; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Humans; Mice; Mice, Transgenic; Mutation; Presenilin-1; Proteomics; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; tau Proteins; Ubiquinone

β-Amyloid (Aβ)-induced toxicity and oxidative stress have been postulated to play critical roles in the pathogenic mechanism of Alzheimer disease (AD). We investigated the in vivo ability of a mitochondria-targeted antioxidant, MitoQ, to protect against Aβ-induced toxicity and oxidative stress in a Caenorhabditis elegans model overexpressing human Aβ. Impairment of electron transport chain (ETC) enzymatic activity and mitochondrial dysfunction are early features of AD. We show that MitoQ extends lifespan, delays Aβ-induced paralysis, ameliorates depletion of the mitochondrial lipid cardiolipin, and protects complexes IV and I of the ETC. Despite its protective effects on lifespan, healthspan, and ETC function, we find that MitoQ does not reduce DCFDA fluorescence, protein carbonyl levels or modulate steadystate ATP levels or oxygen consumption rate. Moreover, MitoQ does not attenuate mitochondrial DNA (mtDNA) oxidative damage. In agreement with its design, the protective effects of MitoQ appear to be targeted specifically to the mitochondrial membrane and our findings suggest that MitoQ may have therapeutic potential for Aβ- and oxidative stress-associated neurodegenerative disorders, particularly AD.

Topics: Adenosine Triphosphate; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Caenorhabditis elegans; Disease Models, Animal; Electron Transport Chain Complex Proteins; Gene Expression; Humans; Longevity; Mitochondria; Mitochondrial Membranes; Organophosphorus Compounds; Oxidative Stress; Oxygen Consumption; Protein Carbonylation; Reactive Oxygen Species; Transgenes; Ubiquinone

A water-soluble formulation of CoQ10 (WS-CoQ10) was shown to stabilize mitochondria and prevent oxidative stress-induced neuronal death. Presenilin-1 (PS-1)-mutated Alzheimer's Disease (AD) fibroblasts (PSAF) were used for studying the effects of PS-1 mutation. PS-1 mutation correlated to increased reactive oxygen species (ROS) production and stress induced premature senescence (SIPS) in PSAF; WS-CoQ10 treatment decreased ROS generation, increased population doublings, and postponed SIPS. Treated PSAF had higher PCNA expression, and lower levels of MnSOD, p21, p16Ink4A, and Rb. WS-CoQ10 caused the resumption of autophagy in PSAF. Thus, WS-CoQ10 as inhibitor of SIPS and ameliorator of autophagy could be an effective prophylactic/therapeutic agent for AD.

Topics: Aging; Alzheimer Disease; Cells, Cultured; Female; Fibroblasts; Humans; Male; Presenilin-1; Stress, Physiological; Ubiquinone; Vitamins

Neurogenesis in the adult brain is important for memory and learning, and the alterations in neural stem cells (NSCs) may be an important part of Alzheimer's disease pathogenesis. The phosphatidylinositol 3-kinase (PI3K) pathway has been suggested to play an important role in neuronal cell survival and is highly involved in adult neurogenesis. Recently, coenzyme Q10 (CoQ10) was found to affect the PI3K pathway. We investigated whether CoQ10 could restore amyloid β (Aβ)25-35 oligomer-inhibited proliferation of NSCs by focusing on the PI3K pathway. To evaluate the effects of CoQ10 on Aβ25-35 oligomer-inhibited proliferation of NSCs, NSCs were treated with several concentrations of CoQ10 and/or Aβ25-35 oligomers. BrdU labeling, Colony Formation Assays, and immunoreactivity of Ki-67, a marker of proliferative activity, showed that NSC proliferation decreased with Aβ25-35 oligomer treatment, but combined treatment with CoQ10 restored it. Western blotting showed that CoQ10 treatment increased the expression levels of p85α PI3K, phosphorylated Akt (Ser473), phosphorylated glycogen synthase kinase-3β (Ser9), and heat shock transcription factor, which are proteins related to the PI3K pathway in Aβ25-35 oligomers-treated NSCs. To confirm a direct role for the PI3K pathway in CoQ10-induced restoration of proliferation of NSCs inhibited by Aβ25-35 oligomers, NSCs were pretreated with a PI3K inhibitor, LY294002; the effects of CoQ10 on the proliferation of NSCs inhibited by Aβ25-35 oligomers were almost completely blocked. Together, these results suggest that CoQ10 restores Aβ25-35 oligomer-inhibited proliferation of NSCs by activating the PI3K pathway.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Proliferation; Cell Survival; Cells, Cultured; Neural Stem Cells; Neurogenesis; Neuroprotective Agents; Peptide Fragments; Phosphatidylinositol 3-Kinases; Rats, Sprague-Dawley; Signal Transduction; Ubiquinone

Glucagon-like peptide-1 (GLP-1) is an endogenous intestinal peptide that enhances glucose-stimulated insulin secretion. Its natural cleavage product GLP-1(9-36)(amide) possesses distinct properties and does not affect insulin secretion. Here we report that pretreatment of hippocampal slices with GLP-1(9-36)(amide) prevented impaired long-term potentiation (LTP) and enhanced long-term depression induced by exogenous amyloid β peptide Aβ((1-42)). Similarly, hippocampal LTP impairments in amyloid precursor protein/presenilin 1 (APP/PS1) mutant mice that model Alzheimer's disease (AD) were prevented by GLP-1(9-36)(amide). In addition, treatment of APP/PS1 mice with GLP-1(9-36)(amide) at an age at which they display impaired spatial and contextual fear memory resulted in a reversal of their memory defects. At the molecular level, GLP-1(9-36)(amide) reduced elevated levels of mitochondrial-derived reactive oxygen species and restored dysregulated Akt-glycogen synthase kinase-3β signaling in the hippocampus of APP/PS1 mice. Our findings suggest that GLP-1(9-36)(amide) treatment may have therapeutic potential for AD and other diseases associated with cognitive dysfunction.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Association Learning; CA3 Region, Hippocampal; Disease Models, Animal; Drug Evaluation, Preclinical; Excitatory Postsynaptic Potentials; Fear; Female; Glucagon-Like Peptide 1; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Male; Memory Disorders; Mice; Mice, Transgenic; Mitochondria; Neuronal Plasticity; Nootropic Agents; Organophosphorus Compounds; Peptide Fragments; Peptides; Presenilin-1; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; Ubiquinone

Increased oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD). A large body of evidence suggests that mitochondrial dysfunction and increased reactive oxygen species occur prior to amyloid-β (Aβ) deposition. Coenzyme Q10 (CoQ10), a component of the mitochondrial electron transport chain, is well characterized as a neuroprotective antioxidant in animal models and human trials of Huntington's disease and Parkinson's disease, and reduces plaque burden in AβPP/PS1 mice. We now show that CoQ10 reduces oxidative stress and amyloid pathology and improves behavioral performance in the Tg19959 mouse model of AD. CoQ10 treatment decreased brain levels of protein carbonyls, a marker of oxidative stress. CoQ10 treatment resulted in decreased plaque area and number in hippocampus and in overlying cortex immunostained with an Aβ42-specific antibody. Brain Aβ42 levels were also decreased by CoQ10 supplementation. Levels of amyloid-β protein precursor (AβPP) β-carboxyterminal fragments were decreased. Importantly, CoQ10-treated mice showed improved cognitive performance during Morris water maze testing. Our results show decreased pathology and improved behavior in transgenic AD mice treated with the naturally occurring antioxidant compound CoQ10. CoQ10 is well tolerated in humans and may be promising for therapeutic trials in AD.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Behavioral Symptoms; Cognition Disorders; Enzyme-Linked Immunosorbent Assay; Exploratory Behavior; Gene Expression Regulation; Humans; Maze Learning; Mice; Mice, Transgenic; Motor Activity; Motor Skills; Mutation; Neuroblastoma; Peptide Fragments; Protein Carbonylation; Time Factors; Ubiquinone; Vitamins

Considerable evidence suggests that mitochondrial dysfunction and oxidative stress contribute to the progression of Alzheimer's disease (AD). We examined the ability of the novel mitochondria-targeted antioxidant MitoQ (mitoquinone mesylate: [10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cycloheexadienl-yl) decyl triphenylphosphonium methanesulfonate]) to prevent AD-like pathology in mouse cortical neurons in cell culture and in a triple transgenic mouse model of AD (3xTg-AD). MitoQ attenuated β-amyloid (Aβ)-induced neurotoxicity in cortical neurons and also prevented increased production of reactive species and loss of mitochondrial membrane potential (Δψ(m)) in them. To determine whether the mitochondrial protection conferred by MitoQ was sufficient to prevent the emergence of AD-like neuropathology in vivo, we treated young female 3xTg-AD mice with MitoQ for 5 months and analyzed the effect on the progression of AD-like pathologies. Our results show that MitoQ prevented cognitive decline in these mice as well as oxidative stress, Aβ accumulation, astrogliosis, synaptic loss, and caspase activation in their brains. The work presented herein suggests a central role for mitochondria in neurodegeneration and provides evidence supporting the use of mitochondria-targeted therapeutics in diseases involving oxidative stress and metabolic failure, namely AD.

Topics: Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Animals; Animals, Newborn; Antioxidants; Caspases; Cell Death; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Glial Fibrillary Acidic Protein; Gliosis; Glutathione; Humans; Lipid Peroxidation; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Neurons; Organophosphorus Compounds; Oxidative Stress; Peptide Fragments; Retention, Psychology; Rhodamines; Space Perception; Time Factors; Tyrosine; Ubiquinone

To investigate the possibility that mitochondrial oxidative damage, oxidative DNA damage or both contribute to the neurodegenerative process of Alzheimer's disease (AD), we employed high-performance liquid chromatography using an electrochemical detector to measure the concentrations of the reduced and oxidized forms of coenzyme Q-10 (CoQ-10) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the cerebrospinal fluid (CSF) of 30 patients with AD and in 30 age-matched controls with no neurological disease. The percentage of oxidized/total CoQ-10 (%CoQ-10) in the CSF of the AD group (78.2 +/- 18.8%) was significantly higher than in the control group (41.3 +/- 10.4%) (P < 0.0001). The concentration of 8-OHdG in the CSF of AD patients was greater than in the CSF of controls (P < 0.0001) and was positively correlated with the duration of illness (r(s) = 0.95, P < 0.0001). The %CoQ-10 was correlated with concentrations of 8-OHdG in the CSF of AD patients (r(s) = 0.66, P < 0.001). The present study suggests that both mitochondrial oxidative damage and oxidative DNA damage play important roles in the pathogenesis of early AD development.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Brain; Brain Chemistry; Deoxyguanosine; DNA Damage; Female; Free Radicals; Humans; Male; Middle Aged; Mitochondria; Mitochondrial Diseases; Nerve Degeneration; Oxidative Stress; Ubiquinone

We previously reported that coenzyme Q10 (CoQ10) could reduce intracellular deposition in an aged transgenic mouse model. Here, we further tested the effect of CoQ10 on amyloid plaque in an amyloid precursor protein/presenilin 1 transgenic mouse model of Alzheimer's disease (AD). By using immunohistochemistry and magnetic resonance imaging to determine the burden of amyloid plaque, we found that oral administration of CoQ10 can efficiently reduce the burden of the plaques in this mouse model. These data demonstrate that in addition to reducing intracellular deposition of Abeta, CoQ10 can also reduce plaque pathology. Our study further supports the use of CoQ10 as a therapeutic candidate for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebral Cortex; Disease Models, Animal; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Mice; Mice, Transgenic; Neuroprotective Agents; Plaque, Amyloid; Presenilin-1; Ubiquinone; Vitamins

Membrane-associated oxidative stress has been implicated in the synaptic dysfunction and neuronal degeneration that occurs in Alzheimer's disease (AD), but the underlying mechanisms are unknown. Enzymes of the plasma membrane redox system (PMRS) provide electrons for energy metabolism and recycling of antioxidants. Here, we show that activities of several PMRS enzymes are selectively decreased in plasma membranes from the hippocampus and cerebral cortex of 3xTgAD mice, an animal model of AD. Our results that indicate the decreased PMRS enzyme activities are associated with decreased levels of coenzyme Q(10) and increased levels of oxidative stress markers. Neurons overexpressing the PMRS enzymes (NQO1 or cytochrome b5 reductase) exhibit increased resistance to amyloid β-peptide (Aβ). If and to what extent Aβ is the cause of the impaired PMRS enzymes in the 3xTgAD mice is unknown. Because these mice also express mutant tau and presenilin-1, it is possible that one or more of the PMRS could be adversely affected by these mutations. Nevertheless, the results of our cell culture studies clearly show that exposure of neurons to Aβ1-42 is sufficient to impair PMRS enzymes. The impairment of the PMRS in an animal model of AD, and the ability of PMRS enzyme activities to protect neurons against Aβ-toxicity, suggest enhancement PMRS function as a novel approach for protecting neurons against oxidative damage in AD and related disorders.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Animals; Cell Membrane; Cerebral Cortex; Hippocampus; Male; Mice; Mice, Transgenic; Neurons; Oxidation-Reduction; Oxidative Stress; 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

Increasing evidence suggests that Alzheimer's disease (AD) is associated with oxidative damage that is caused in part by mitochondrial dysfunction. Here we investigated the feasibility of modifying Alzheimer pathology with the mitochondrial antioxidant coenzyme Q (CoQ). Exogenous CoQ protected MC65 neuroblastoma cells from amyloid-beta protein precursor C-terminal fragment (APP CTF)-induced neurotoxicity in a concentration dependent manner, with concentrations of 6.25 microM and higher providing near complete protection. Dietary supplementation with CoQ at a dose of 10 g/kg diet to C65/Bl6 mice for one month significantly suppressed brain protein carbonyl levels, which are markers of oxidative damage. Treatment for one month with 2 g lovastatin/kg diet, which interferes with CoQ synthesis, resulted in a significant lowering of brain CoQ10 levels. Mitochondrial energetics (brain ATP levels and mitochondrial membrane potential) were unaffected by either CoQ or lovastatin treatment. Our results suggest that oral CoQ may be a viable antioxidant strategy for neurodegenerative disease. Our data supports a trial of CoQ in an animal model of AD in order to determine whether a clinical trial is warranted.

Topics: Adenosine Triphosphate; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Antioxidants; Brain; Cell Line, Tumor; Dietary Supplements; Female; Humans; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Transgenic; Ubiquinone

One of the neuropathological features of Alzheimer's disease (AD) is the deposition of senile plaques containing beta-amyloid (A beta). There is limited evidence for the treatment to arrest A beta pathology of AD. In our present study, we tested the effect of coenzyme Q10 (CoQ10), an endogenous antioxidant and a powerful free radical scavenger, on A beta in the aged transgenic mice overexpressing Alzheimer presenilin 1-L235P (leucine-to-proline mutation at codon 235, 16-17 months old). The treatment by feeding the transgenic mice with CoQ10 for 60 days (1,200 mg kg(-1) day(-1)) partially attenuated A beta overproduction and intracellular A beta deposit in the cortex of the transgenic mice compared with the age-matched untreated transgenic mice. Meanwhile, an increased oxidative stress reaction was detected as evidenced by elevated level of malondialdehyde (MDA) and decreased activity of superoxide dismutase (SOD) in the transgenic mice relative to the wild-type mice, and supplementation of CoQ10 partially decreased MDA level and upregulated the activity of SOD. The results indicate that oxidative stress is enhanced in the brain of the transgenic mice, that this enhancement may further promote A beta 42 overproduction in a vicious formation, and that CoQ10 would be beneficial for the therapy of AD.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebral Cortex; Coenzymes; Female; Humans; Malondialdehyde; Mice; Mice, Transgenic; Oxidative Stress; Peptide Fragments; Plaque, Amyloid; Point Mutation; Presenilin-1; Superoxide Dismutase; Ubiquinone; Vitamins

Tau aggregation is a common feature of tauopathies such as Alzheimer disease (AD). In AD, tau assembles into fibrillar polymers; it may also be present in other aberrant aggregates, including Hirano bodies. The mechanisms leading to tau polymerization in vivo are not understood. In this study, we found that coenzyme Q (ubiquinone) facilitates tau aggregation after binding to tau molecules at the region of the tau molecule involved in self-assembly. Consequently, after tau-tau interactions, this region is masked in fibrillar tau polymers. Further in vitro studies showed that ubiquinone facilitates the interaction of tau protein with actin to form structures that are morphologically similar to Hirano bodies. Finally, studies in AD brains show that Hirano bodies react with an antibody raised against ubiquinone, indicating that ubiquinone is a component of Hirano bodies. Taken together, the in vitro models and findings in AD suggest that in the presence of ubiquinone, Hirano bodies may result from the interaction of actin and other proteins, including tau.

Topics: Actins; Aged; Alzheimer Disease; Brain; Female; Humans; Inclusion Bodies; Male; Micronutrients; Microscopy, Immunoelectron; Neurofibrillary Tangles; Neurons; Neurotoxins; Polymers; Protein Binding; tau Proteins; Ubiquinone

We have investigated the propensity to form fibrillar aggregates of a variety of fragments and variants of the tau protein under the influence of a tau fibrillization inducer: coenzyme Q(0). To better identify fibrillization hotspots, we compare the polymerization propensity of tau fragments containing the sequence of putative hotspots with that of tau variants with that same sequence deleted. We also investigate the effects of biologically occurring modifications such as phosphorylation and deamidation. We found that residues 305 to 335 are essential for in vitro tau fibrillization. Residues 306 to 311 facilitate in vitro assembly, but are not sufficient to mimic the in vivo fibrillization of tau. Furthermore, the propensity of the 306-311 sequence to form fibrils is highly decreased by chemical modifications of tyrosine 310 that are commonly found in vivo.

Topics: Alzheimer Disease; Amino Acid Sequence; Base Sequence; Codon; Humans; Molecular Sequence Data; Neurofibrillary Tangles; Peptide Fragments; Plasmids; Polymerase Chain Reaction; Restriction Mapping; tau Proteins; 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

The neurotoxic effects and influence of beta-amyloid peptide (Abeta)(1-42) on membrane lipids and nicotinic acetylcholine receptors (nAChRs) in human SH-SY5Y neuroblastoma cells were investigated in parallel. Exposure of the cultured cells to varying concentrations of Abeta(1-42) evoked a significantly decrease in cellular reduction of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5,diphenyl tetrazolium bromide), together with enhanced lipid peroxidation and protein oxidation. Significant reductions in the total contents of phospholipid and ubiquinone-10, as well as in the levels of the alpha3 and alpha7 subunit proteins of nAChRs were detected in cells exposed to Abeta(1-42). In contrast, such treatment had no effect on the total cellular content of cholesterol. Among these alterations, increased lipid peroxidation and decreased levels of cellular phospholipids were most sensitive to Abeta(1-42), occurring at lower concentrations. In addition, when SH-SY5Y cells were pretreated with the antioxidant Vitamin E, prior to the addition of Abeta(1-42), these alterations in neurotoxicity, oxidative stress, composition of membrane lipids and expression of nAChRs were partially prevented. These findings suggest that stimulation of lipid peroxidation by Abeta may be involved in eliciting the alterations in membrane lipid composition and the reduced expression of nAChRs associated with the pathogenesis of AD.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Alzheimer Disease; Amyloid beta-Peptides; Cholesterol; Dose-Response Relationship, Drug; Humans; Lipid Peroxidation; Membrane Lipids; Neurons; Oxidation-Reduction; Oxidative Stress; Peptide Fragments; Phospholipids; Receptors, Nicotinic; Tumor Cells, Cultured; Ubiquinone; Vitamin E

Oxidative stress is suggested to play an important role in the pathogenesis of Parkinson's disease (PD). However, no elevation of plasma oxidative stress marker has been reported. We measured percent content of the oxidized form of coenzyme Q10 in total coenzyme Q10 (%CoQ-10) because %CoQ-10 has been shown to be a sensitive marker of oxidative stress. A slight but significant elevation in %CoQ-10 was observed in PD patients when compared with age/gender-matched normal subjects, suggesting elevated systemic oxidative stress in PD patients.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Chromatography, High Pressure Liquid; Coenzymes; Electrochemistry; Female; Humans; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Plasma; Statistics, Nonparametric; Ubiquinone

We compared serum levels of coenzyme Q10 and the coenzyme Q10/cholesterol ratio in 44 patients with Alzheimer's disease (AD), 17 patients with vascular dementia (VD), and 21 matched controls. The mean serum coenzyme Q10 and cholesterol levels and the coenzyme Q10/cholesterol ratio of patients with AD or VD did not differ significantly from those of controls. Coenzyme Q10 levels and coenzyme Q10/cholesterol ratio of AD or VD patients were not correlated with age, age at onset, duration of the disease or scores of the MiniMental State Examination. These results suggest that these values are not related with the risk for AD or VD.

Topics: Aged; Alzheimer Disease; Cholesterol; Coenzymes; Dementia, Vascular; Female; Humans; Male; Oxidative Stress; Risk Factors; Ubiquinone

The distribution patterns of amyloid precursor protein (APP) fragments were studied immunocytochemically in the rat brain before, after 10 min ischemia and following treatment by idebenone. Six months after brain ischemia intense staining for APP appeared in extra- and intracellular space. These findings indicate that APP is involved in the degeneration process of brain neuronal and glial cells following ischemia-reperfusion injury and anti-oxidative therapy did not prevent and/or stop this phenomenon.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloidosis; Animals; Antioxidants; Benzoquinones; Cell Death; Drug Evaluation, Preclinical; Extracellular Space; Female; Free Radicals; Heart Arrest; Hypoxia-Ischemia, Brain; Intracellular Fluid; Neuroglia; Neurons; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Wistar; Reperfusion Injury; Risk Factors; Ubiquinone

Amyloid beta-peptide (A beta), the major constituent of the senile plaques in the brains of patients with Alzheimer's disease, is cytotoxic to neurons and has a central role in the pathogenesis of the disease. Previous studies have suggested that oxidative stress is involved in the mechanisms of A beta-induced neurotoxicity in vitro. In the present study, we examined whether oxidative stress contributes to learning and memory deficits caused by continuous intracerebroventricular infusion of A beta-(1-42). In the A beta-(1-42)-infused rats, spontaneous alternation behaviour in a Y-maze and spatial memory in a water maze task were significantly impaired, as compared with A beta-(40-1)-infused control rats. The retention of passive avoidance learning was also significantly impaired by treatment with A beta-(1-42). Potent antioxidants idebenone and alpha-tocopherol prevented the behavioural deficits in Y-maze and water maze, but not passive avoidance, tasks in A beta-(1-42)-infused rats when they were repeatedly administered by mouth once a day from 3 days before the start of A beta infusion to the end of behavioural experiments. Lipid peroxide levels in the hippocampus and cerebral cortex of A beta-(1-42)-infused rats did not differ from those in control animals, and neither idebenone nor alpha-tocopherol affected the lipid peroxide levels. These results suggest that treatment with antioxidants such as idebenone and alpha-tocopherol prevents learning and memory deficits caused by A beta.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Avoidance Learning; Benzoquinones; Brain Chemistry; Drug Interactions; Injections, Intraventricular; Lipid Peroxidation; Locomotion; Male; Maze Learning; Memory; Nerve Degeneration; Neurotoxins; Oxidative Stress; Peptide Fragments; Rats; Rats, Wistar; Ubiquinone; Vitamin E

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

During aging the human brain shows a progressive increase in levels of dolichol, a reduction in levels of ubiquinone, but relatively unchanged concentrations of cholesterol and dolichyl phosphate. In a neurodegenerative disease, Alzheimer's disease, the situation is reversed with decreased levels of dolichol and increased levels of ubiquinone. The concentrations of dolichyl phosphate are also increased, while cholesterol remains unchanged. This study shows that the isoprenoid changes in Alzheimer's disease differ from those occurring during normal aging and that this disease cannot, therefore, be regarded as a result of premature aging. The increase in the sugar carrier dolichyl phosphate may reflect an increased rate of glycosylation in the diseased brain and the increase in the endogenous anti-oxidant ubiquinone an attempt to protect the brain from oxidative stress, for instance induced by lipid peroxidation.

Topics: Adult; Aged; Aged, 80 and over; Aging; Alzheimer Disease; Animals; Brain Chemistry; Cells, Cultured; Cholesterol; Dolichol Phosphates; Dolichols; Humans; Lipid Metabolism; Mevalonic Acid; Middle Aged; Nerve Degeneration; Polyisoprenyl Phosphates; Rats; Ubiquinone

Topics: Alzheimer Disease; Citric Acid; Coenzymes; Drug Therapy, Combination; Female; Ferrous Compounds; Humans; Mental Status Schedule; Middle Aged; Pyridoxine; Ubiquinone

The lipid compositions of 10 different brain regions from patients affected by Alzheimer's disease/senile dementia of Alzheimer's type were analyzed. The total phospholipid amount decreased somewhat in nucleus caudatus and in white matter. The cortical areas that are morphologically affected by Alzheimer's disease, i.e., frontal and temporal cortex and the hippocampus, showed elevated contents of lipid solvent-extractable phosphatidylinositol. Sphingomyelin content was decreased in regions rich in myelin. There was a 20-50% decrease in dolichol amount in all investigated parts of the brain, but no change was seen in the polyisoprenoid pattern. Levels of alpha-unsaturated polyprenes were decreased in Alzheimer brains. Dolichyl-phosphate content increased in most regions, up to 100%. In both control and Alzheimer tissue almost all of the dolichyl-phosphate was covalently bound, apparently through glycosylation. Cholesterol amounts were highly variable but mostly unchanged, whereas ubiquinone concentrations increased by 30-100% in most regions in brains affected by Alzheimer's disease. These results demonstrate that both phospholipids and neutral lipids are modified in brains affected by Alzheimer's disease/senile dementia of Alzheimer's type.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain Chemistry; Cholesterol; Dolichol Phosphates; Dolichols; Humans; Lipid Metabolism; Lipids; Nerve Tissue Proteins; Phospholipids; Ubiquinone

The lipid compositions of various regions of the human brain were investigated during aging and in Alzheimer's disease. The phospholipid amounts and compositions remained unchanged during aging. There were, however, considerable differences both in phospholipid composition and amount when the various regions were compared. The level of dolichol increased severalfold in all regions up to the age of 70, but there was no further elevation thereafter. The ubiquinone level decreased significantly in all parts of the brain upon aging. In Alzheimer's disease, the dolichol level was decreased in all regions, and particularly, in those affected by the disease. In contrast, the dolichyl-P concentration increased in those regions that exhibited morphological changes. There was no modification in cholesterol distribution, but a significant elevation in ubiquinone content was observed in most regions. The only phospholipid whose level was elevated was phosphatidylinositol, and only in those parts of the brain that were affected. The content of polyunsaturated fatty acids in phosphatidylethanolamine was greatly decreased in connection with the disease, with a parallel increase in the saturated portion. The results indicate that Alzheimer's disease results in specific and significant changes in the levels of lipid products of the mevalonate pathway in the brain.

Topics: Aged; Aging; Alzheimer Disease; Brain Chemistry; Cholesterol; Dolichol Phosphates; Dolichols; Fatty Acids; Humans; Membrane Lipids; Mevalonic Acid; Middle Aged; Phosphatidylinositols; Phospholipids; Ubiquinone

Topics: Acetylcholine; Aging; Alzheimer Disease; Animals; Cerebrovascular Circulation; Dementia; gamma-Aminobutyric Acid; Humans; Microcirculation; Naloxone; Oxygen Consumption; Tetrahydrofolates; Ubiquinone