Coenzyme Q10 Helps Prevent Alzheimer’s
Along with Galantamine …
The neuroprotective effect of CoQ10 could be due to its microglia inhibitory mechanism
There is considerable evidence showing that mitochondrial dysfunction and oxidative damage play a key role in the development of neurodegenerative disease, including both Alzheimer’s disease (AD) and Parkinson’s disease (PD). This relationship has been known for many years.
CoQ10 Efficacy Along with Other Antioxidants
In a review published eleven years ago (back in 2004), both mitochondrial dysfunction and oxidative damage were found to contribute to amyloid-beta (Aβ) damage in AD.1 (See larger image) Also discussed in this paper were the cumulative findings that PD is associated with abnormalities in the electron transport gene as well as oxidative damage, and that the efficacy of Coenzyme Q10(CoQ10) along with other antioxidants might help treat both AD and PD. CoQ10, an atypical lipophilic antioxidant, is an essential component of the mitochondrial electron-transport chain. It is involved in the manufacturing of adenosine triphosphate(ATP) and has been linked with improving cognitive functions. ATP is used in cells as a coenzyme and is often called the “molecular unit of currency” of intracellular energy transfer. ATP transports chemical energy within cells for metabolism.
and oxidative damage were found to
contribute to amyloid-beta
damage in AD.
Mitochondrial Damage and AD
As far back as 1991 (how old were you then?), research showed that CoQ 10 levels—studied in AD patients—were greatly reduced (approximately 50%) compared with controls.2 In 2000, a researcher announced that a role for mitochondrial dysfunction in neurodegenerative disease is gaining increasing support.3 Furthermore, it was concluded that if mitochondrial dysfunction plays a role in neurodegenerative diseases, then therapeutic strategies such as coenzyme Q10 and creatine may be useful in attempting to slow the disease process.
Evidence indicated that AD
is associated with oxidative damage
that is caused in part by
mitochondrial dysfunction.
Vitamin E and CoQ10: Better Together for Learning Deficits
In another paper, the findings suggested that concurrent supplementation of alpha-tocopherol (vitamin E) with CoQ10 is more likely to be effective as a potential treatment for age-related learning deficits than supplementation with CoQ10 or alpha-tocopherol alone. 4
The same year, it was recognized that inhibition of the formation of amyloid-beta (Aβ) fibrils, as well as the destabilization of preformed Aβ fibrils in the central nervous system would be attractive therapeutic targets for the treatment of AD. 5
CoQ10 Helps Prevent Oxidative Damage in the Brain
Dietary supplementation with CoQ10
at a dose of 10 g/kg diet to mice for
one month—the human equivalent is
65 mg/day for a 176 lb human—
significantly suppressed brain protein
carbonyl levels, which are markers of
oxidative damage.
In a 2008 article published in the Journal of Alzheimer’s Disease, more evidence indicated that AD is associated with oxidative damage that is caused in part by mitochondrial dysfunction (see Fig. 1).6 Is it possible to modify Alzheimer’s pathology with the nutrient CoQ10, the researchers asked? What they found is that CoQ10protected neuroblastoma cells from Aβ protein precursor C-terminal fragment-induced neurotoxicity in a concentration-dependent manner, with concentrations of 6.25 microM and higher providing near complete protection.
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MitoQ: A Targeting Form of CoQ10
In the 1990s, two New Zealand biochemists, desiring to get more CoQ10 more efficiently into mitochondria came up with an idea.1 They considered that a portion of the mitochondria’s electrochemical activity is employed to unceasingly pump protons out through their membranes. Thus the mitochondria maintain a negative electric potential compared to the rest of the cell. Furthermore, anything with a positive charge is drawn into the mitochondria, and if it’s not a proton, it won’t be pumped right back out again. Aha! So the two biochemists created a molecule that combined CoQ10 at one end with a chemical “tugboat” at the other, so as to create two propellers within the mitochondria. The chemical tugboat, called TPP (tri-phenyl phosphonium), had been developed many years earlier in a Russian lab of Vladimir Skulachev.2 Connecting the tugboat to CoQ10 is a simple carbon chain that prevents interference between the chemical properties of the two ends.3 Once the understanding had been achieved, synthesis followed, but not before years of testing, progressing through cell cultures, animal models, and eventually humans. This process, called targeting, eventually led to nearly all of newly created synthesized molecules taken up by mitochondria.4 This means that very low doses can result in very high effectiveness. The manufacturers called this achievement MitoQ. MitoQ is considered an unapproved new drug by the FDA, and confiscations have been reported. References
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Dietary supplementation with CoQ10 at a dose of 10 g/kg diet to mice for one month—the human equivalent is 65 mg/day for a 176 lb human—significantly suppressed brain protein carbonyl levels, which are markers of oxidative damage.
It is widely known that one of the neuropathological features of AD is the deposition of senile plaques containing Aβ. In a study reported in 2008, researchers tested CoQ10, an endogenous antioxidant and a powerful free radical scavenger on Aβ in aged transgenic mice overexpressing Alzheimer presenilin 1, a mutation involved in the majority of early onset, autosomal dominant Alzheimer’s disease.7
Mitochondrial dysfunction is widely
implicated in the pathogenesis of AD.
The transgenic mice fed CoQ10 for 60 days (at 1,200 mg/kg/day) partially reduced Aβ overproduction and intracellular Aβ deposit in the cortex of the transgenic mice compared with the age-matched untreated transgenic mice.
Supplementation with CoQ10 also decreased malondialdehyde levels and upregulated the activity of superoxide dismutase. These results indicate that CoQ10 would be beneficial for the therapy of AD.
Increased autophagic degradation of
mitochondria has also been
observed in AD.
Mitochondrial Dysfunction Is Implicated in AD
Mitochondrial dysfunction is widely implicated in the pathogenesis of AD. Evidence for mitochondrial dysfunction in AD pathogenesis comes from impaired activities of the three key Krebs cycle enzyme complexes: pyruvate dehydrogenase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase. These impairments have been observed in postmortem AD brain and fibroblasts from AD patients.8 Also, reduced respiratory chain complex I activity was found in platelets and lymphocytes from AD patients and in postmortem brain tissue.
More recently, increased autophagic degradation (autophagy is the natural, destructive mechanism that disassembles, through a regulated process, unnecessary or dysfunctional cellular components) of mitochondria has also been observed in AD. In a review, several bioenergetic agents are discussed that improve mitochondrial function including CoQ10, creatine, nicotinamide, riboflavin, and lipoic acid, which are being tested for their neuroprotective efficacy in neurodegenerative disorders.
Animal studies aside, 2009 marks the year of a human study measuring the ratio of the oxidized and reduced forms of CoQ10 related to the pathogenesis of AD.9 The findings in living AD patients suggest a possible role for oxidized CoQ10 in the pathogenesis of the early stage of AD development.
The findings in living AD patients
suggest a possible role for oxidized
CoQ10 in the pathogenesis of the
early stage of AD development.
Improved Behavior in Transgenic AD Mice
Another mouse study found decreased pathology and improved behavior in transgenic AD mice treated with the naturally occurring antioxidant compound CoQ10.10 First off, CoQ10 decreased brain levels of protein carbonyls, a marker of oxidative stress. Then, CoQ10 resulted in decreased plaque area and number in the hippocampus and in overlying cortex immune-stained with an Aβ42-specific antibody.
Also, brain Aβ42 levels were decreased by CoQ10 supplementation, while levels of amyloid-β protein precursor β-carboxyterminal fragments were decreased. Significantly, CoQ10-treated mice showed improved cognitive performance during Morris water maze testing. The results showed decreased pathology and improved behavior in transgenic AD mice treated with CoQ10.
Significantly, CoQ10-treated mice
showed improved cognitive
performance during
Morris water maze testing.
CoQ10 Neuroprotective Effect
Researchers from Panjab University in Chandigarh, India recently reported that the neuroprotective effect of CoQ10 could be due to its microglia inhibitory mechanism along with its mitochondrial restoration and anti-oxidant properties. Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system. One way to control neuroinflammation is to inhibit microglial activation.
Intrahippocampal Aβ (1-42) was administered in rats (not easy to do in humans) to induce the equivalency of many aspects of AD in humans. The intent of the study was to investigate the neuroprotective potential of CoQ10 and its modulation by minocycline (a microglial inhibitor) against Aβ (1-42), which induced cognitive dysfunction in the lab animals. Minocycline is a broad-spectrum tetracycline antibiotic drug that penetrates the brain. Minocycline has many side effects (see below).
One way to control
neuroinflammation is to inhibit
microglial activation.
Following this, galantamine (2 mg/kg), CoQ10 (20 and 40 mg/kg), minocycline (50 and 100 mg/kg) and their combinations were administered for a period of 21 days. The scientists measured various neurobehavioral parameters followed by biochemical factors, including acetylcholinesterase (AChE) levels, proinflammatory markers (TNF-α), and mitochondrial respiratory enzyme complexes (I-IV). Histopathological examinations were also assessed. In clinical medicine, histopathology refers to the examination of a biopsy or surgical specimen by a pathologist.
Aβ (1-42) administration significantly impaired cognitive performance in the Morris water maze performance test, caused oxidative stress, raised AChE levels, caused neuroinflammation, mitochondrial dysfunction and histopathological alterations, as compared to sham treatment.
Treatment with CoQ10 (20 and 40 mg/kg) and minocycline (50 and 100 mg/kg) alone for 21 days significantly improved cognitive performance as evidenced by reduced transfer latency and increased time spent in the target quadrant—treading water over the submerged platform area, after it had been removed.
The neuroprotective effect of CoQ10
could be due to its microglia
inhibitory mechanism along with its
mitochondrial restoring and
anti-oxidant properties.
The rats were also found to have reduced AChE activity (that’s one of the benefits of galantamine), oxidative damage (reduced lipoperoxides, nitrite level, and restored SOD, catalase and glutathion peroxidase levels), TNF-α level, while restoring mitochondrial respiratory enzyme complex (I, II, III, IV) activities and histopathological alterations as compared to Aβ (1-42) treated animals. Furthermore, the combination of minocycline (50 and 100 mg/kg) with CoQ10 (20 and 40 mg/kg) significantly modulates the protective effect of CoQ10 dose dependently as compared to their effect alone. The neuroprotective effect of CoQ10 could be due to its microglia inhibitory mechanism along with its mitochondrial restoring and anti-oxidant properties.
The Findings of the Indian Study
In the Indian study, the administration of Aβ (1-42) significantly impaired cognitive performance in the Morris water maze test as indicated by delayed transfer latency time to reach the platform (taking longer to find the platform), and getting to where the platform had been, suggesting that Aβ (1-42) induced impairment in spatial learning and memory.
Aβ (1-42) also caused significant increase in AChE activity indicating an impairment of the cholinergic system, a measure of cholinergic dysfunction. Also, the study revealed that, administration of Aβ (1-42) resulted in a significant increase in MDA; nitrite concentration, depleted reduced glutathione, SOD and catalase activities in Aβ (1-42)-treated animals. Thus, Aβ (1-42) instigated oxidative stress.
Aβ (1-42) induced impairment in
spatial learning and memory.
Altered Activity of Mitochondrial Respiratory Enzymes
The study also indicated that Aβ (1-42) accumulation significantly altered the activity of mitochondrial respiratory enzymes (NADH dehydrogenase, succinate dehydrogenase activity, and cytochrome C oxidase). Aβ (1-42) accumulation also impaired the neural cell availability of Aβ (1-42)-treated animals as compared to sham treated animals. This suggested mitochondrial dysfunction.
Aβ (1-42) also caused significant
increase in AChE activity.
Moreover, the study found that administration of Aβ (1-42) significantly increased TNF-α level in Aβ (1-42)-treated animals as compared to sham-treated animals, indicating the role of neuroinflammation in the Aβ (1-42) model of cognitive dysfunction. Previous studies have also demonstrated the neuroprotective potential of both CoQ10 and minocycline in different neurological conditions. However, their mechanism of action is not yet clear. Supporting the above, the Indian study demonstrated the neuroprotective effect of CoQ10 and minocycline against Aβ (1-42)-induced cognitive dysfunction. Therefore, beneficial treatment of CoQ10 along with minocycline in neurodegenerative disorders including AD with multiple pathogenic properties can be achieved through drugs targeting multiple pathways or polytherapeutic interventions directed toward specific aspect of the neurodegenerative phenotype, the composite of an organism's observable characteristics or traits.
Aβ (1-42) instigated oxidative stress.
CoQ10 Facilitates ATP Synthesis
CoQ10 improves cognitive function, upregulates mitochondrial function, and facilitates ATP synthesis. Supplementation of CoQ10 increases brain endogenous CoQ10 content and acts as an antioxidant against free radical generation and oxidative modification of biomolecules. It also provides significant enhancement in patients with neurological disorders.
Aβ (1-42) accumulation significantly
altered the activity of mitochondrial
respiratory enzymes.
The major role of CoQ10 is to transfer electrons between redox components of the electron transfer chain, to create a proton gradient across the inner mitochondrial membrane, drive ATP formation, and act as a powerful antioxidant that is protective against oxidative stress (see Fig. 2).
Thus, CoQ10 in vivo protects against oxidation of lipids, proteins, and DNA. Previous evidence has suggested an intimate link between excessive generation of reactive oxygen and reactive nitrogen species and development of hippocampal neuronal death.
In the present study, chronic treatment with CoQ10 (20 and 40 mg/kg) in Aβ (1- 42)-treated animals significantly lessened impairment of spatial learning and memory task performance, AChE activities, mito-oxidative damage, restored mitochondrial respiratory enzyme complex activities and TNF-α level suggesting its anti-oxidant, mitochondrial-restoring and anti-inflammatory action as compared to Aβ (1-42)-treated animals.
Minocycline, a semi-synthetic second-generation tetracycline analog has both antimicrobial and anti-inflammatory activity. It also possesses efficacy against a broad range of neurological disorders with a good clinical safety record. Previous studies on animal models showed that minocycline prevented the release of cytochrome C (a facilitation protein operating in the mitochondria electron transport chain) in isolated mitochondria, suggesting mitochondria as a direct target of minocycline. Minocycline also inhibits the formation of Aβ aggregates and disassembles the preformed fibrils.
Aβ (1-42) accumulation also impaired
the neural cell availability.
Furthermore, chronic treatment with minocycline improved spatial learning and memory task performance, reduced AChE activities, mito-oxidative damage, restored mitochondrial respiratory enzyme complex activities and attenuated TNF-α level, suggesting its anti-oxidant, mitochondrial restoring and anti-inflammatory action as compared to Aβ (1-42)-treated animals.
Furthermore, chronic treatment with CoQ10 in combination with minocycline significantly enhanced their neuroprotective effect (lessening spatial learning and memory performance task), AChE activities, mito-oxidative damage, restored the mitochondrial respiratory enzyme activities and TNF-α level) suggesting their synergistic action. In the present study, Aβ (1-42) administration caused significant damage in the hippocampal and cortical region of the brain that plays important roles in learning and memory.
CoQ10 improves cognitive function,
upregulates mitochondrial function,
and facilitates ATP synthesis.
For the histopathological evaluation, the hippocampal region was targeted and it was observed that brain areas of Aβ (1-42) treated animals had significantly higher density of pyknotic neuronal cells suggesting degeneration and disrupted functioning of the hippocampal neurons. Besides, CoQ10 in combination with minocycline, significantly improved cell layer organization, reduced density of pyknotic (the irreversible condensation of chromatin in the nucleus of a cell undergoing necrosis or apoptosis) cells and pyramidal cell in the CA1 and CA3 regions of the hippocampus as compared to their effects alone in Aβ (1-42) treated rat brain hippocampus.
Adverse Effects of Minocycline
In support, these results highlight anti-oxidant, anti-inflammatory and mitochondrial restoring properties of CoQ10. However, when in combination with minocycline, the neuroprotective effect against Aβ (1-42)-induced cognitive dysfunction is increased. Nonetheless, minocycline is a drug that has many adverse effects, some of which may be serious, including confusion, diarrhea, dizziness or lightheadedness, severe headache, severe stomach pain, and many more. It is not recommended for AD or PD. However, its mechanism—microglia inhibition, which is also true for CoQ10—could lead to other discoveries such as herbal medicines and dietary supplements. These may include catechol-containing antioxidants.
Furthermore, since both galantamine and CoQ10 alone were shown to have positive effects and work by different mechanisms, the total effects are likely to be additive.
References
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- Beal MF.Mitochondria, NO and neurodegeneration. Biochem Soc Symp. 1999;66:43-54.
- McDonald SR1, Sohal RS, Forster MJ. Concurrent administration of coenzyme Q10 and alpha-tocopherol improves learning in aged mice. Free Radic Biol Med.2005 Mar 15;38(6):729-36.
- Ono K1, Hasegawa K, Naiki H, Yamada M. Preformed beta-amyloid fibrils are destabilized by coenzyme Q10 in vitro. Biochem Biophys Res Commun. 2005 Apr 29;330(1):111-6.
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- Yang X, Yang Y, Li G, Wang J, Yang ES. Coenzyme Q10 attenuates beta-amyloid pathology in the aged transgenic mice with Alzheimer presenilin 1 mutation. J Mol Neurosci. 2008 Feb;34(2):165-71.
- Chaturvedi RK, Beal MF. Mitochondrial approaches for neuroprotection. Ann N Y Acad Sci. 2008 Dec;1147:395-412.
- Isobe C, Abe T, Terayama Y. Increase in the oxidized/total coenzyme Q-10 ratio in the cerebrospinal fluid of Alzheimer’s disease patients. Dement Geriatr Cogn Disord. 2009;28(5):449-54.
- Dumont M, Kipiani K, Yu F, Wille E, Katz M, Calingasan NY, Gouras GK, Lin MT, Beal MF. Coenzyme Q10 decreases amyloid pathology and improves behavior in a transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis.2011;27(1):211-23. doi: 10.3233/JAD-2011-110209.
- Singh A, Kumar A. Microglial Inhibitory Mechanism of Coenzyme Q10 Against Aβ (1-42) Induced Cognitive Dysfunctions: Possible Behavioral, Biochemical, Cellular, and Histopathological Alterations. Front Pharmacol. 2015 Nov 9;6:268.