Is Astaxanthin Effective for Alzheimer's Disease?

 Alzheimer's disease (AD) is a common neurodegenerative disease characterized by gradual memory loss and progressive cognitive dysfunction that seriously affects the ability to live independently. AD is a common neurodegenerative disease characterized by gradual memory loss and progressive cognitive dysfunction that severely affects the ability to lead an independent life. 47 million people suffer from AD globally, with more than 9.5 million people in China, and the incidence of AD in elderly people aged 60 years old or above has reached 5.3%, showing a rapid growth trend.AD is the third most serious disease that causes disability and death in the elderly after cardio-cerebral vascular diseases and malignant tumors.The treatment of AD is a medical problem in the world, and so far, no safe and effective drug can stop the progression of the AD course [1]. In recent years, a large number of studies have found that natural astaxanthin (astaxan-thin, AST) can easily cross the blood-brain barrier and has potential therapeutic effects on neurodegenerative diseases such as AD, such as inhibition of the aggregation of amyloid ß peptide (Aß), antioxidant, anti-neuroinflammation, and anti-apoptosis, etc. [2]. This paper briefly summarizes the neuroprotective effects of AST on AD and its mechanism.

 

1 Chemical and biological properties of astaxanthin

AST is a fat-soluble carotenoid pigment widely found in nature, chemically known as 3,3'-dihydroxy-4,4'-diketo-beta-β-β'-carotene, with the molecular formula C40 H52 O4 (Figure 1). Natural AST is synthesized by a number of phytoplankton, algae, bacteria and fungi, which are consumed by shrimps, crabs, fish, birds, chickens and ducks and stored in the body. Red algae are the organisms with the highest content of AST in the nature known to date, and it is one of the best sources of natural AST. AST has a unique molecular structure, containing conjugated double bonds, hydroxyl and ketone groups. It has both lipophilic and hydrophilic properties, and its conjugated double bonds can terminate the chain reaction of free radicals in the organism with cells and tissues by giving the electrons to react with the free radicals, so AST has a strong antioxidant effect. Its antioxidant ability is as high as that of the free radicals in cells and tissues. Therefore, AST has a strong antioxidant effect, and its antioxidant capacity is 550 times that of vitamin E, 10 times that of β-carotene, and can prevent the peroxidation of unsaturated fatty acids[2] . Synthetic AST is slightly different from natural AST in molecular structure, and its antioxidant ability is obviously weakened.AST is easily absorbed and bioavailable in oily solvents, and it is mainly transferred to the epithelial cells of the small intestine by transcellular membrane diffusion, and directly transported to the corresponding organs or tissues by fat molecules to play its role. The unesterified AST is bound to the coeliac particles and transported to the liver through the lymphatic system, where it is bound to lipoproteins and then transported to the corresponding target organs[3] .

 

According to the literature, AST has anti-tumor, anti-inflammatory, immunity-enhancing, exercise fatigue-relieving, eye and central nervous system protection, and prevention of cardiovascular and cerebral vascular diseases, etc. In 1999, the U.S. Food and Drug Administration (FDA) approved the use of natural AST as a dietary supplement in pharmaceuticals and cosmetics. A number of toxicity studies have confirmed that AST has no acute or chronic toxic side effects such as teratogenicity, embryotoxicity and reproductive toxicity[5] . A safe dose of AST of up to 80 mg/kg has been demonstrated in animal studies. The oral dose of AST in human clinical trials at home and abroad is mostly in the range of 4~40 mg/d, and it shows a quantitative effect relationship within a certain dose range[6] .

 

2 Neuroprotective effects of astaxanthin in Alzheimer's disease and its mechanisms

In recent years, numerous studies have demonstrated that AST can exert neuroprotective effects against central nervous system injuries, such as AD, by inhibiting Aß aggregation, antioxidant, anti-inflammatory, and anti-apoptotic mechanisms through the blood-brain barrier [7] (Figure 2) [2,8]. Experimental studies have shown that AST can inhibit Aß-induced decrease in cell viability, intracellular reactive oxygen species (ROS) production, and apoptosis in neuronal cell lines, as well as inhibit Aß-induced decrease in mitochondrial membrane potential, release of cytochrome C, and decrease the expression of inflammatory factors, which suggests that AST has a neuroprotective effect on AD at the cellular level[4]. Fanaee-Danesh applied AST to in vitro primary porcine brain capillary endothelial cells. Fanaee-Danesh used primary porcine brain capillary endothelial cells (pBCEC) and 3xTg AD mice to study the effects of AST on Aß processing, production and translocation, and found that AST down-regulated the transcription and activity of BACE1, a component of Aß production, and enhanced Aß clearance [9]. Recently, it has been reported in the literature[10] that AST can significantly reverse the pathological processes of AD, such as Aß42 deposition, pTau formation, reduced total glutathione (GSH) and small albumin (PV)-positive neuronal deficits, and improve the memory impairment of experimental animals. Lakey-Beitia's computational structural drug design analysis and molecular docking simulation have revealed that there are special structural linkages between the carotenoids including AST and Aß through hydrogen bonding and other structural features. Aß, which interacts with AST through special structures such as hydrogen bonding, has the functions of anti-amyloid formation and inhibition of Aß aggregation, and has a potential role in the prevention of AD[11] .

 

The central nervous system is a high oxygen-consuming tissue, vulnerable to damage by oxygen radicals and other reactive oxygen species, AST is a potent natural antioxidant that can directly antagonize the damage of reactive oxygen species to the central nervous system.AST can also inhibit Aß-induced production of oxygen radicals and inhibit calcium endocytosis[12] . Many studies have found that AST inhibits oxidative stress injury by activating the Nrf2/ARE signaling pathway, promoting the breakdown of Nrf2 and Keap1, initiating the nuclear translocation of Nrf2, upregulating the expression of antioxidant enzymes, such as heme oxygenase-1, and mitigating the damage caused by reactive oxygen species to the CNS, thus exerting neuroprotective effects.10 AST has also been shown to have an anti-inflammatory effect on the nervous system by blocking the upstream cytokines, such as cytokines, and by inhibiting the production of Aß-induced oxygen free radicals, and inhibiting calcium inward flow. AST also has anti-inflammatory effects, mainly by preventing the upregulation of the upstream cytokine macrophage migration inhibitory factor (MIF), antagonizing the N-methyl D-aspartate (NMDA) receptor, and blocking the NF-κB signaling pathway[13] , and thus inhibiting the release of cytokines, such as interleukin 1β (IL- 1β), IL-10, tumor necrosis factor-α (TNF- α), and intercellular adhesion molecule 1 (ICAM1)[8] . In addition to resisting oxidative stress damage and anti-inflammation, AST also exerts anti-apoptotic effects by blocking p-ERK/ERK, cytochrome C, and caspase3,9[14] . In addition, AST inhibits glutamate-induced excitatory cytotoxicity by reducing caspase activation, mitochondrial dysfunction and modulating Akt/GSK-3β signaling[15] .

 

In conclusion, the neuroprotective mechanism of AST is not completely clear and further studies are needed. Recently, a randomized, double-blind, placebo-controlled clinical trial was reported to evaluate the effects of a dietary supplement containing AST and sesamin on the cognitive function of patients with mild cognitive impairment (MCI). The results showed a significant improvement in psychomotor and processing speeds in the treatment group compared with the placebo group, and it was concluded that the daily supplementation of AST and sesamin could improve cognitive functions related to comprehension and the ability to perform complex tasks quickly and accurately[16] . It was concluded that daily supplementation with AST and sesamin can improve cognitive functions related to comprehension and the ability to perform complex tasks quickly and accurately[16] .

 

3 Prospects for clinical application of astaxanthin against Alzheimer's disease

In summary, AST has the following advantages: (1) AST has multiple neuroprotective effects on AD through inhibiting Aß aggregation, antioxidant, inhibiting neuroinflammation and apoptosis, and improving cognitive function; (2) as a high-level nutraceutical, AST is safe; (3) AST is a fat-soluble small molecule compound, which is easy to cross the blood-brain barrier. Therefore, AST has multiple neuroprotective effects on AD and has good clinical prospects for AD prevention and treatment.

 

References .

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