Study of the Therapeutic Effects of COQ10 in Alzheimer's Disease

 With the increase of life expectancy, Alzheimer's disease (AD) has become one of the major diseases affecting the quality of life in the later years of human beings, with Alzheimer's disease (AD) accounting for about 70% of the cases of Alzheimer's disease[1] . AD is a common degenerative disease of the central nervous system, whose main pathological features are β-amyloid deposits and neurofibrillary tangles composed of highly phosphorylated Tau proteins.

 

AD is a common degenerative disease of the central nervous system, and its main pathological features are age spots composed of β-amyloid deposits and neurofibrillary tangles composed of highly phosphorylated Tau proteins. The prevalence of AD increases gradually with age, and the severe cognitive impairment obviously affects the quality of life of patients and brings great pressure to families and society. The exact etiology of AD has not yet been fully elucidated, but studies have pointed out that oxidative stress, mitochondrial dysfunction, neuroinflammation and cerebrovascular dysfunction may be involved in the occurrence and development of AD, among which oxidative stress and mitochondrial dysfunction have received extensive attention from scholars at home and abroad.

 

As a fat-soluble antioxidant, COQ10 regulates the body's antioxidant enzyme system, scavenges oxygen free radicals, and reduces oxidative stress [2], and has been found to have neuroprotective effects as well. A brief review of the therapeutic effects of coenzyme Q10 on AD is presented.

 

1 Antioxidant Effects of COQ10

Mitochondria as the main place of cellular energy production, energy production is mainly realized through the transfer of high-energy electrons in the mitochondria. However, the production of adenosine triPhosPhate (ATP) by electron transfer is accompanied by the generation of reactive oxygen species (ROS). Normally, antioxidant enzymes (e.g., proteins such as thiols, reduced glutathione, α-tocopherol, etc.) are present in the body to scavenge ROS[3] .

 

In AD, the antioxidant enzyme system has been found to be weakened. When the antioxidant enzyme system is weakened to the extent that it is insufficient to scavenge the generated ROS, oxidative stress occurs and oxidative damage is caused to cellular components, which includes mutation of mitochondria DNA (mtDNA), carboxylation of proteins, lipid peroxidation, etc. [4]. Mutations of mtDNA damage the electron transport chain, thus causing respiratory chain complexes, which can lead to the formation of a complex of respiratory chains. Mutations in mtDNA damage the electron transport chain, resulting in reduced activity of the respiratory chain complex and reduced proton pumping, leading to a decrease in the mitochondrial membrane potential (ΔΨm). When ΔΨm falls below a certain threshold, the mitochondrial transition Pore (mPTP) opens, triggering cell death through apoptosis or necrosis [5].

 

Coenzyme Q10 has been found to have a number of molecular bases for the treatment of neurodegenerative diseases. Coenzyme Q10 has been shown to inhibit oxidative damage to mitochondria and can act as an antioxidant on several levels. Coenzyme Q10 scavenges oxygen radicals by interacting with α-tocopherol. In addition, the activation of coenzyme Q10 as a cofactor of mitochondrial uncoupling proteins reduces the production of free radicals[6] .

 

In addition to its radical scavenging activity, Coenzyme Q10 prevents apoptotic cell death by blocking the binding of the pro-apoptotic gene Bax to mitochondria and by inhibiting the activation of the mitochondrial permeability transition (MPT)[7] . Further, Coenzyme Q10 blocked the release of cytochrome c and the activation of cysteine-9, but not cysteine-8, which are the substrates for the activation of endogenous and exogenous apoptotic pathways, respectively, suggesting that Coenzyme Q10 blocks apoptosis through the inhibition of endogenous pathways, but not exogenous pathways [8].

 

2 Neuroprotective Effects of COQ10

2.1 Coenzyme Q10 Reduces β-Amyloid Neurotoxicity

The deposition of β-amyloid (Aβ) can cause damage to neuronal and synaptic functions and lead to neuronal degeneration.L235P PS-1 transgenic old mice overproduced β-amyloid polypeptide-42 (Aβ42) and oxidative stress, and also deposited a large amount of Aβ42 in the cells.An intervention study of L235P PS-1 transgenic old mice using coenzyme Q10 showed that coenzyme Q10 effectively reduced Aβ42 production and accumulation and suppressed oxidative stress[9] .

 

Coenzyme Q10 effectively reduced Aβ42 production and intracellular accumulation and suppressed oxidative stress in L235P PS-1 transgenic aged mice[9] . In vivo and in vitro studies have shown that Aβ is located in the mitochondrial cristae of neurons[10] , and that Aβ accumulation can cause elevated ROS and mitochondrial dysfunction, leading to mPTP opening and cytochrome c release, and resulting in cellular damage and death[11,12] . A novel mitochondria-targeted ubiquinone derivative (MitoQ) prevented the excessive production of reactive substances and the decrease of Δψm in Aβ-induced cortical neurons, suggesting that MitoQ is protective against Aβ-induced cortical neuronal damage[13] .

 

2.2 Coenzyme Q10 Restores the Activity of Mitochondrial Energy Metabolizing Enzymes   

Respiratory chain complexes (I, II, III and IV) are essential for mitochondrial production of life-sustaining ATP, and it has been found that respiratory chain complex IV is decreased in the mitochondria of patients with AD, which is one of the reasons for energy hypometabolism in AD patients [14].

 

Ng LF et al. found that MitoQ treatment group showed a significant increase in respiratory chain complexes IV and I compared with the untreated group, suggesting that MitoQ has a protective effect on the mitochondrial respiratory chain [15]. Ng LF et al. showed that the respiratory chain complexes IV and I were significantly increased in the MitoQ-treated group compared with the untreated group, indicating that MitoQ has a protective effect on the mitochondrial respiratory chain[15] . In another study, Singh A et al. found that 40 mg/kg of coenzyme Q10 restored the reduced activity of mitochondrial respiratory enzyme complexes (I, II, III, IV) in the hippocampus and cerebral cortex of Aβ1-42-treated rats [16].

 

2.3 Coenzyme Q10 Inhibits the Inflammatory Response

Inflammation has been found to play an important role in the pathogenesis of AD. Choi H et al. found that coenzyme Q10 protected neuronal cells from Aβ25-35-induced neurotoxicity in a concentration-dependent manner by increasing the expression of phosphatidylinositol 3-kinase P85α (P85αPI3K), phosphorylated Akt, phosphorylated glycogen synthase kinase-3β, and heat shock transcription factors, all of which are related to neuronal cell survival, in cortical neurons treated for 48 hr with different concentrations of coenzyme Q10 in response to Aβ fragment 25-35-induced damage.

 

COQ10 protected neuronal cells from Aβ25-35-induced neurotoxicity in a concentration-dependent manner by increasing the levels of phosphatidylinositol 3-kinase P85α (P85αPI3K), phosphorylated Akt, phosphorylated glycogen synthase kinase-3β, and heat-shock transcription factors, which are associated with neuronal cell survival, and by decreasing death signals, including cytoplasmic cytochrome c and activated cysteine-3, which were mediated by the enzyme phosphatidylinositol 3-hydroxy kinase (PIHK), and the cytosolic cytosolic cytosol. This protective effect was blocked by the phosphatidylinositol 3-hydroxy kinase (PI3K) inhibitor LY294002, suggesting that the neuroprotective effect of coenzyme Q10 on Aβ25-35-induced neurotoxicity can be mediated by the activation of the PI3K-Akt signaling pathway[17] .

 

In addition, nuclear factor kaPPa-B (NF-κB) has been reported to be closely related to Aβ-induced neuroinflammation. Li et al. found that coenzyme Q10 reduced neuroinflammation in Aβ25-35-induced PC12 cells by preventing Aβ25-35-induced degradation of IκBα (one of the members of the NF-κB family of inhibitory proteins) and nuclear translocation of P65, inhibiting prostaglandin E2 (PGE2) production and cyclooxygenase-2 (COX-2) protein expression. The study showed that coenzyme Q10 reduced neuroinflammation by preventing Aβ25-35-induced degradation of IκBα (a member of the NF-κB inhibitory protein family) and nuclear translocation of P65, and by inhibiting the production of prostaglandin E2 (PGE2) and the expression of cyclo-oxygenase-2 (COX-2), suggesting that the inhibition of NF-κB signaling pathway by COQ10 in PC12 cells may result in the down-regulation of pro-inflammatory mediators, and thus produce anti-inflammatory effects [18].

 

3 Coenzyme Q10 and the Treatment of AD

Although the exact etiology and pathogenesis of AD are not fully understood, there is a large body of evidence suggesting that oxidative stress-induced production of reactive substances and mitochondrial dysfunction are involved in the onset and progression of AD. So derberg et al. analyzed ubiquinone levels in 10 different brain regions in patients with AD/SDAT, and found that ubiquinone levels were significantly increased in most of the brain regions [19]. The elevated levels of ubiquinone in AD/SDAT may reflect increased oxidative stress.  Isobe et al. reported that the percentage of oxidized/total coenzyme Q10 in the cerebrospinal fluid of patients with early to mid-stage AD was significantly higher than that of controls, and that this percentage was negatively correlated with disease duration, suggesting that an increased percentage of oxidized/total coenzyme Q10 is associated with the pathogenesis of early AD [20].

 

Current researchers are divided on the therapeutic effects of coenzyme Q10 on AD. Dumont et al. found that COQ10 reduced brain oxidative stress and β-amyloid levels and improved cognitive behaviors in Tg19959 mice [21]. McManus et al. found that MitoQ reduced oxidative stress, Aβ accumulation, astrocyte proliferation, synaptic loss, and cysteoaspartic enzyme activation, preventing the decline in cognitive performance in 3xTg-AD mice [22].

 

McManus et al. found that MitoQ reduced oxidative stress, Aβ accumulation, astrocyte proliferation, synaptic loss and cysteinyl asparagin activation, and prevented cognitive decline in 3xTg-AD mice [22]. Singh et al. studied β-amyloid 1-42 (Aβ1-42)-treated AD rats, and found that 40 mg/kg of CoQ10 significantly attenuated oxidative damage, restored mitochondrial respiratory enzymes and histopathological alterations, and reduced acetylcholinesterase (AChE) activity, and improved cognitive performance [16]. Muthukumaran et al. studied the effects of a water-soluble preparation of coenzyme Q10 (Ubisol-Q10) in transgenic AD mice and found that Ubisol-Q10 significantly reduced circulating Aβ peptide and inhibited the formation of cerebral Aβ plaques compared with the untreated group, as well as improved long-term memory and preserved workspace memory [23].

 

COQ10 has also been clinically tested in the treatment of AD. Galasko et al. evaluated the efficacy of coenzyme Q10 in 78 patients with mild-to-moderate AD treated with 400 mg of coenzyme Q10 three times a day for 16 weeks using oxygenated stress markers and cognitive function scores, and found that no significant improvement was observed compared with the placebo group [24]. This may be related to the uneven distribution of coenzyme Q10 and its difficulty in crossing the blood-brain barrier and reaching neuronal mitochondria. Idebenone, a synthetic analog of coenzyme Q10, has been used in neuroprotective studies in AD. Senin et al. studied the effects of twice-daily ibuprofen 45 mg for 4 months in 102 elderly AD patients and found that ibuprofen significantly improved memory, attention, and behavior in AD patients [25].

 

Bergamasco et al. conducted a multicenter, randomized, placebo-controlled, double-blind trial of ibenzoquinone treatment for 90 d in 92 patients with AD and found that ibenzoquinone improved memory, attention, and orientation and slowed the progressive deterioration of the disease.26 Weyer et al. studied the effects of ibenzoquinone treatment in 300 patients with mild-to-moderate AD dementia who were randomly assigned to either ibenzoquinone (30 mg, 90 mg) or a placebo 3 times daily for 6 months and found an overall improvement in the Clinical Global Impression Scale (CGI) in the 3-times daily ibenzoquinone 90 mg group. Weyer et al. examined the effects of a 6-month treatment of 300 patients with mild-to-moderate AD dementia randomly assigned to 3 times daily ibenzoquinone (30 mg, 90 mg) or placebo, and found that the 3 times daily ibenzoquinone 90 mg group showed an overall improvement in Clinical Global Impression (CGI), and significant improvements in AD Cognitive Assessment Scale (ADAS-Cog) and Non-Cognitive Functioning (ADAS-Noncog) scores[27] .

 

Gutzmann et al. conducted a 2-year study of patients with mild-to-moderate AD. Gutzmann et al. conducted a two-year randomized, double-blind study in patients with mild-to-moderate AD, and found that the two ibenzoquinone groups (90 and 120 mg three times daily) scored significantly higher than the placebo group on a number of cognitive measures, and that the 120 mg group scored better than the 90 mg group [28]. However, not all studies have been positive.A 1-year multicenter, double-blind, placebo-controlled study by Thal LJ et al. conducted a randomized controlled trial of 3 daily doses of ibuprofen 120, 240, or 360 mg in 536 patients with suspected AD, and found no significant differences in ADAS-Cog and Clinical Gross Impression Change (CGIC) scores among the 4 groups [29].

 

4 Safety of Coenzyme Q10

The high safety profile of coenzyme Q10 in the treatment of AD has been demonstrated in clinical trials. Coenzyme Q10 has been shown to be relatively well tolerated at doses of 200-3000mg/day. When plasma levels of coenzyme Q10 reach 2400 mg/d, mild side effects such as headache, heartburn and other gastrointestinal symptoms may occur, in addition to fatigue, increased involuntary movements and asymptomatic elevation of liver enzymes [30].

 

AD is a common degenerative disease of the central nervous system, and its symptoms such as cognitive decline, personality change and behavioral impairment seriously affect the quality of life of AD patients, and bring great pressure to the family and the society, so it is very urgent to find effective drugs to treat AD patients. Coenzyme Q10, with its anti-oxidative stress and neuroprotective effects, has been shown to improve cognitive decline in animals with AD in both cellular and animal studies.

 

Due to the uneven distribution of exogenous coenzyme Q10, it is not easy to cross the blood-brain barrier and penetrate into the mitochondria of neurons, which leads to the poor therapeutic effect in AD patients. Idebenone, a synthetic analog of coenzyme Q10, has been proved to have good therapeutic efficacy in patients with early to middle stage of AD, and MitoQ, as a ubiquinone derivative targeting the mitochondria, shows powerful antioxidant effects, and it also has shown good pharmacokinetic behaviors in the phase I clinical trials of AD patients. MitoQ, as a mitochondria-targeting ubiquinone derivative, showed strong antioxidant effects and good pharmacokinetic behavior in a phase I clinical trial in AD patients. Therefore, more basic and clinical studies are needed to provide strong evidence that coenzyme Q10 and its analogs are effective in the treatment of AD.

 

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