coenzyme-q10 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

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

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

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

Aging is the major risk factor for Alzheimer's disease (AD), and cognitive and memory impairments are common among the elderly. Interestingly, coenzyme Q10 (Q10) levels decline in the brain of aging animals. Q10 is a substantial antioxidant substance, which has an important role in the mitochondria.. We assessed the possible effects of Q10 on learning and memory and synaptic plasticity in aged β-amyloid (Aβ)-induced AD rats.. In this study, 40 Wistar rats (24-36 months old; 360-450 g) were randomly assigned to four groups (n = 10 rats/group)-group I: control, group II: Aβ, group III: Q10; 50 mg/kg, and group IV: Q10+Aβ. Q10 was administered orally by gavage daily for 4 weeks before the Aβ injection. The cognitive function and learning and memory of the rats were measured by the novel object recognition (NOR), Morris water maze (MWM), and passive avoidance learning (PAL) tests. Finally, malondialdehyde (MDA), total antioxidant capacity (TAC), total thiol group (TTG), and total oxidant status (TOS) were measured.. Q10 improved the Aβ-related decrease in the discrimination index in the NOR test, spatial learning and memory in the MWM test, passive avoidance learning and memory in the PAL test, and long-term potentiation (LTP) impairment in the hippocampal PP-DG pathway in aged rats. In addition, Aβ injection significantly increased serum MDA and TOS levels. Q10, however, significantly reversed these parameters and also increased TAC and TTG levels in the Aβ+Q10 group.. Our experimental findings suggest that Q10 supplementation can suppress the progression of neurodegeneration that otherwise impairs learning and memory and reduces synaptic plasticity in our experimental animals. Therefore, similar supplemental Q10 treatment given to humans with AD could possibly provide them a better quality of life.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Child, Preschool; Disease Models, Animal; Hippocampus; Humans; Long-Term Potentiation; Maze Learning; Memory Disorders; Neuronal Plasticity; Quality of Life; Rats; Rats, Wistar

A growing body of evidence suggests that vitamin supplements play a role in the prevention of cognitive decline. The objective of the present cross-sectional study was to evaluate the relationship between cognitive ability and folic acid, B vitamins, vitamin D (VD) and Coenzyme Q10 (CoQ10) supplementation. The sample consisted of 892 adults aged above 50 who were assessed for their cognitive status in the Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (China) from July 2019 to January 2022. According to the degree of cognitive impairment, the subjects were divided into a normal control (NC) group, subjective cognitive decline (SCD) group, mild cognitive impairment (MCI) group and Alzheimer's disease (AD) group. The results indicated a lower risk of AD in the daily VD-supplemented subjects with MCI compared to those who were not supplemented; a lower risk of cognitive impairment in those with normal cognitive who consumed VD, folic acid or CoQ10 on a daily basis compared those who did not; and a lower risk of cognitive impairment in subjects with normal cognitive performance who consumed B vitamin supplements, either daily or occasionally, compared to those who did not. The correlation was independent of other factors that potentially affect cognition, such as education level, age, etc. In conclusion, our findings confirmed a lower prevalence of cognitive impairment in those who took vitamins (folic acid, B vitamins, VD, CoQ10) daily. Therefore, we would recommend daily supplementation of vitamins (folic acid, B vitamins, VD, CoQ10), especially group B vitamins, as a potential preventive measure to slow cognitive decline and neurodegeneration in the elderly. However, for the elderly who have already suffered from cognitive impairment, VD supplementation may also be beneficial for their brains.

Topics: Aged; Alzheimer Disease; China; Cognition; Cognitive Dysfunction; Cross-Sectional Studies; Dietary Supplements; East Asian People; Feeding Behavior; Folic Acid; Humans; Middle Aged; Vitamin A; Vitamin B 12; Vitamin B Complex; Vitamin D

Excess amyloid beta (Aβ) and oxidative stress (OS) are inextricable hallmarks of the neuronal damage associated Alzheimer's disease. Aβ-induced cognitive and memory dysfunctions are mediated through different signalling pathways as phosphatidylinositol-3-kinase (PI3K) and their downstream intermediates including protein-kinase-B, known as Akt, glycogen-synthase-kinase-3β (GSK-3β), cAMP-response-element-binding-protein (CREB), brain-derived-neurotrophic factor (BDNF) and tropomyosin-related-kinase receptor-B (TrKB). The current work aims to investigate the protective potentials of CoQ10 against scopolamine (Scop)-induced cognitive disability and the contribution of PI3K/Akt/GSK-3β/CREB/BDNF/TrKB in the neuroprotection effects.. The chronic co-administration of CQ10 (50, 100 and 200 mg/kg/day i.p.) with Scop in Wistar rats for 6 weeks were assayed both behaviourally and biochemically.. CoQ10 ameliorated the Scop-induced cognitive and memory defects by restoring alterations in novel object recognition and Morris water maze behavioural tests. CoQ10 favourably changed the Scop-induced deleterious effects in hippocampal malondialdehyde, 8-hydroxy-2' deoxyguanosine, antioxidants and PI3K/Akt/GSK-3β/CREB/BDNF/TrKB levels.. These results exhibited the neuroprotective effects of CoQ10 on Scop-induced AD and revealed its ability to inhibit oxidative stress, amyloid deposition and to modulate PI3K/Akt/GSK-3β/CREB/BDNF/TrKB pathway.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain-Derived Neurotrophic Factor; Glycogen Synthase Kinase 3 beta; Oxidative Stress; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Scopolamine Derivatives; Tropomyosin

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

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

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

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 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

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

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

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

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

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

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

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