Carotenoids in Alzheimer's Disease


Although identification of the molecular mechanisms involved in Azheimer’s disease (AD) pathogenesis has proven elusive, oxidative stress and neuronal apoptosis play essential roles (Mines et al., 2011; Chen and Zhong, 2014; Wang et al., 2019). Whereas the potential risk factors include age, education, and family history of the disease, the presumed risk factors are smoking, social isolation, and physical inactivity (Alzheimer’s Association, 2017; Livingston et al., 2017; Nolan et ah, 2018). Although many drugs and bioactive compounds which have been tested for their efficacy against AD showed some symptomatic relief, substantial therapeutic compounds to combat AD have still to be discovered (Nolan et ah, 2018).

Many plants used extensively in traditional medicine contain carotenoids, monoterpenes and polyphenol compounds, which all play pivotal roles in the amelioration of neurodegenerative diseases (Khazdair et ah, 2019). Since more than 95% of sporadic AD patients were found to lack adequate amyloid-beta (A(3) scavenging, a plethora of drugs have been targeted at A(3 scavenging (Yuan et ah, 2019). Hancornia speciosa, a fruit tree extensively used in traditional medicine in Brazil, has been found to contain important carotenoids, such as p-carotene and lycopene (El-Agamey et ah, 2004; Van den berg et ah, 2000; Dos Santos et ah, 2018). These have been found to show appreciable biological and physiological functions (Dos Santos et ah, 2018). Mounting evidence recommends that dietary supplementation with specific nutritional compounds can mitigate the AD risk (Solfrizzi et ah, 2017; Nolan et ah, 2018). A healthy Japanese or Mediterranean diet significantly decreases the risk of AD (Scarmeas et ah, 2006; Ozawa et ah, 2013; Nolan et ah, 2018). Nevertheless, the exact foodstuffs which decrease the risk of developing AD are still unclear (Scarmeas et ah, 2009; Psaltopoulou et ah, 2013; Sofi et ah, 2014; Singh et ah, 2014; Nolan et ah, 2018).


Adequate intake of xanthophyll carotenoids, such as lutein, zeaxanthin, and meso- zeaxanthin, decreases AD risk (Loef and Walach, 2012; Min and Min, 2014; Feart et ah, 2016; Nolan et ah, 2018). In addition, lutein and zeaxanthin intake achieved marked cognitive improvements, even in non-AD people (Johnson et ah, 2008a; Hammond et ah, 2017; Power et ah, 2018; Nolan et ah,

2018) . They were also found to enhance membrane integrity and to contribute to neural efficacy (Bovier and Hammond. 2015; Zamroziewicz et ah, 2016; Lindbergh et ah, 2017; Nolan et ah, 2018). Lutein, zeaxanthin, and meso-zeaxanthin have been found in increased concentrations in the macula (retina), a part of the central nervous system (CNS). They are also found in brain regions such as the hippocampus, cerebellum, and the frontal, temporal, and occipital cortices (Craft et ah, 2004; Johnson et ah, 2013; Nolan et ah, 2018).

Studies have shown that combination treatments between xanthophyll carotenoids (e.g. lutein) and omega-3 fatty acids improved retinal concentrations of xanthophyll in healthy female subjects (Johnson et ah, 2008b; Nolan et ah, 2018). This is due to the enhanced carotenoid uptake and bioavailability when carotenoids are administered in the presence of oils or cholesterol (Van Het Hof et ah, 2000; Nolan et ah, 2018). Although the combination intake of xanthophyll carotenoids and omega-3 fatty acids substantially ameliorated AD symptoms, further studies are needed to corroborate these findings (Nolan et ah, 2018).


Astaxanthin is a red-colored carotenoid pigment, abundantly found in many marine organisms, like crustaceans, microalgae, and krill (Higuera-Ciapara et ah, 2006; Miki, 1991; Alghazwi et ah,

2019) . In addition, it is also present in a small number of plants and yeasts, and in the feathers of a few birds (Hussein et ah, 2006; Alghazwi et ah, 2019). Astaxanthin belongs to the xanthophyll family of carotenoids and is commercially offered isolated from the microalga Haematococcus pluvialis and the yeast Phaffia rhodozyma (Wu et ah, 2015; Alghazwi et ah, 2019). Astaxanthin, being a powerful antioxidant, showed substantial neuroprotective efficacy in the PC12 cell line, which includes neuroblastic cells, against AP25_35-induced toxicity (Chang et ah, 2010; Alghazwi et ah, 2019). In another study, astaxanthin showed substantial inhibition of Ap25_35-induced toxicity in the SH-SY5Y human neuroblastoma cell line by reducing the Bcl-2:Bax ratio, decreasing the rate of apoptosis (Wang et ah, 2010; Alghazwi et ah, 2019). Antioxidant and anti-inflammatory properties of astaxanthin contribute substantially to the protective activity against AD (Zhang et ah, 2014; Wu et ah, 2015; Han et ah, 2019). Astaxanthin has also demonstrated greater protective efficacy against Ap25_35-induced cytotoxicity, compared with that achieved by (3-carotene and canthaxanthin (Chang et ah, 2013; Alghazwi et ah, 2019).

Astaxanthin has received approval from the United States Food and Drug Administration (FDA) as a food supplement (Guerin et ah, 2003; Stewart et ah, 2008; Alghazwi et ah, 2019). In another study, astaxanthin showed reduced memory loss in mice (Han et ah, 2019). Although astaxanthin has low bioavailability, co-intake of lipids may enhance its bioavailability (Alghazwi et ah, 2019). The emulsifier polysorbate 80 also caused a 4-fold increase in the bioavailability of astaxanthin (Odeberg et ah, 2003; Alghazwi et ah, 2019). In another study, Wistar rats, to which 0.5 mg astaxanthin /kg bodyweight was administered, significantly ameliorated AJ3,.42-induced cognitive impairment (Rahman et ah, 2019). Since astaxanthin is not synthesized in humans, it has to be supplemented through diet (Guerin et ah, 2003; Rodriguez-Ruiz et ah, 2018).


Fucoxanthin, a tetraterpenoid, is obtained from brown macro- and microalgae (Peng et ah, 2011; Alghazwi et ah, 2019). It is an orange-colored pigment. Members of the Haptophyta, Phaeophyceae, Bacillariophyceae, and Chrysophyceae are rich in fucoxanthin, which is found in low concentrations in members of the Raphidophyceae, Rhodophyta, and Dinophyta (Takaichi, 2011; Alghazwi et ah, 2019). With oxygen in its functional group, fucoxanthin belongs to the xanthophyll class of carotenoids, distinct from the carotenes (Mikami and Hosokawa, 2013; Alghazwi et ah, 2019). It has been shown to exert numerous health benefits, which include cardioprotective activity (Matsumoto et ah, 2010), anticancer (Kumar et ah, 2013), antioxidant (Sachindra et ah, 2007), antidiabetic (Nishikawa et ah, 2012), and antiobesity effects (Okada et ah, 2008; Alghazwi et ah, 2019). It has also been shown to attenuate A(3M2 -induced toxicity in neurons of the cerebral cortex (Zhao et ah, 2015; Alghazwi et ah, 2019). In line with this, in another study, attenuation of A(3,.42 -aggregation was observed in SH-SY5Y cells in the presence of fucoxanthin (Xiang et ah, 2017; Alghazwi et ah, 2019). The primary protective mechanism of fucoxanthin against the A(3 oligomer was found to involve inhibition of the extracellular signal-regulated kinase (ERK) pathway and induction of the phosphoinositide-3-kinase/protein kinase В (PI3K/Akt) pathway (Lin et ah, 2017; Alghazwi et ah, 2019). Studies on the protective efficacy of marine carotenoids, such as astaxanthin and fucoxanthin, against A(3 aggregation showed that fucoxanthin is more effective than astaxanthin against A(3|.42 aggregation (Alghazwi et ah, 2019).


Crocus sativus (saffron) belongs to the Iridaceae family and has been extensively cultivated and used in India, Iran, Morocco, Greece, Turkey, Italy, Spain, Azarbaijan, Pakistan, Egypt, and China (Bhat and Broker, 1953; Leone et ah, 2018). The active components of saffron include crocin and crocetin, which are atypical carotenoids with a 20-carbon atom chain (unlike the 35-40 carbon atom chains of other carotenoid pigments), with two carboxylic groups on either side (Leone et ah, 2018). Crocins are carotenoids, which exhibit high water solubility due to the occurrence of a sugar moiety (Leone et ah, 2018). Crocetin is an important antioxidant that has been extensively studied for its numerous health benefits (Frank 1961; Leone et ah, 2018). Crocin has shown substantial protection against L-glutamate-induced damage in the HT22 mouse hippocampal neuron cell line by reducing the apoptotic rate, decreasing mitochondrial impairment, and attenuating intracellular reactive oxygen species (ROS) accumulation (Wang et ah, 2019). Therefore, crocin is a potential compound for the treatment of AD by intervening with the oxidative stress-associated apoptosis signaling pathway (Wang et al., 2019).


Retinoic acid (RA) plays an essential role in neuroprotection by impacting on the cell cycle genes. However, it may not avert the abnormal re-entry of neurons into the cell cycle (Ashok et ah, 2019). RA shows substantial neuroprotective efficacy against AD due to its antioxidant, antiapoptotic, antiinflammatory, Ар-decreasing and acetylcholine (Ach) activating properties (Behairi et ah, 2016; Chakrabarti et ah, 2015; Lee et ah, 2009; Moutinho and Landreth, 2017; Niewiadomska-Cimicka et ah, 2017). Bexarotene, a retinoid X receptor (RXR) agonist, mitigated Ap levels in the brain, and ameliorated cognitive function in AD mouse models following a 7-d treatment (Yuan et ah, 2019). Nevertheless, several subsequent studies failed to reproduce these results (Fitz et ah, 2013; Price et ah, 2013; Tesseur et ah, 2013; Veeraraghavulu et ah, 2013; Yuan et ah, 2019).


Lycopene, an aliphatic hydrocarbon carotenoid, is usually isolated from papayas, tomatoes, or watermelons (Heber and Lu, 2002; Mourvaki et ah, 2005; Chen et ah, 2019). It has a protective efficacy, through its substantial anti-inflammatory, antioxidative and antiproliferative activities (Chen et ah, 2019). It also shows appreciable therapeutic efficacy against a number of CNS disorders, such as AD, Parkinson’s disease (PD), Huntington’s disease (HD), epilepsy, cerebral ischemia, and depression (Sandhiret ah, 2010; Qu et ah, 2011; Yu et ah, 2017; Chen et ah, 2019). Lycopene showed remarkable recovery of cognition in transgenic mice with the P301L tau mutation and inhibited Ap- instigated cellular toxicity in cultured neurons (Qu et ah, 2011; Yu et ah, 2017; Chen et ah, 2019). The long-term intake of lycopene (5 mg/kg for 21 d) inhibited Ap,.42-induced caspase activation in the hippocampus of rats (Prakash and Kumar, 2014; Chen et ah, 2019). In another study, lycopene pre-treatment (0.2-0.5 pM) successfully averted ApM2-initiated cellular apoptosis by decreasing ROS generation and mitochondrial impairment (Hwang et ah, 2017; Chen et ah, 2019). Long-term lycopene administration (0.03% w/w) inhibited lipopolysaccharide (LPS)-induced Ap aggregation and BACE1 enhancement (Wang et ah, 2018; Chen et ah, 2019). Additionally, lycopene administration (5 mg/kg for 8 weeks) also inhibited tau hyperphosphorylation at Thr231, Ser235, Ser262, and Ser396 in brain tissues of P301 transgenic mice (Chen et ah, 2019).

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