Carotenoids and Alzheimer’s Disease: An insight into therapeutic role of retinoids in animal models

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  Carotenoids and Alzheimer’s Disease: An insight into therapeutic role of retinoids in animal models
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  Review Carotenoids and Alzheimer’s Disease: An insight into therapeutic roleof retinoids in animal models M. Obulesu a, ⇑ , Muralidhara Rao Dowlathabad b , P.V. Bramhachari c a Department of Biotechnology, Rayalaseema University, Kurnool, Andhra Pradesh, India b Department of Biotechnology, Srikrishnadevaraya University, Anantapur, Andhra Pradesh, India c Department of Biotechnology, Krishna University, Machilipatnam, Andhra Pradesh, India a r t i c l e i n f o  Article history: Received 29 January 2011Received in revised form 16 March 2011Accepted 20 April 2011Available online 7 June 2011 Keywords: Alzheimer’s DiseaseCarotenoidsRetinoic acidAll trans retinoic acidNeuroprotectionAnimal model a b s t r a c t Carotenoids play a pivotal role inpreventionof manydegenerative diseases mediated byoxidative stressincluding neurodegenerative diseases like Alzheimer’s Disease (AD). The involvement of retinoids inphysiology,ADpathologyandtheirtherapeuticroleinvitroandinvivohasbeenextensivelystudied.Thisreview focuses on the role of carotenoids like retinoic acid (RA), all trans retinoic acid (ATRA), lycopeneand  b -carotene in prevention of AD symptoms primarily through inhibition of amyloid beta (A b ) forma-tion, deposition and fibril formation either by reducing the levels of p35 or inhibiting correspondingenzymes. The role of antioxidant micronutrients in prevention or delaying of AD symptoms has beenincluded. This study emphasizes the dietary supplementation of carotenoids to combat AD and warrantsfurther studies on animal models to unravel their mechanism of neuroprotection.   2011 Elsevier B.V. All rights reserved. 1. Introduction Etiology of AD is multifactorial which includes oxidative stress,apoptosis, mutations in genes, redox activity of metals and theiraccumulation (Obulesu et al., 2009, 2011a,b; Obulesu and Rao,2010a,b). Dietary supplementation of carotenoids has been shownto play a pivotal role in preventing various neurodegenerative dis-eases like AD (Mecocci et al., 2002; Haegele et al., 2000).Retinoids being analogues of RA, are active metabolites of vita-minA, andspecific modulators of cell proliferation, differentiation,and morphogenesis in vertebrates (Shudo et al., 2009) (Fig. 1). Medicinalchemistryofthesebioactivecompoundshasbeenexten-sively studied (Shudo et al., 2009; Sporn et al., 1984; Nau andBlaner, 1999; Kagechika, 2002; Kagechika and Shudo, 2005;Dawson, 2004; de Lera et al., 2007; Napoli, 1990). These com-pounds exert protective effect against manifold diseases like acutepromyelocytic leukemia (Wang and Chen, 2008; Miwako andKagechika, 2007), psoriasis (Sardana and Sehgal, 2003; Ishibashi,1995), collagen-induced rheumatoid arthritis and other autoim-mune models (Kuwabara et al., 1996; Nagai et al., 1999; Beehleret al., 2004), atherosclerosis and restenosis of vascular vessels(Wiegman et al., 2000; Fujiu et al., 2005), diabetic retinopathy(Nishikiorietal., 2007a), cataract(Nishikiorietal., 2007b), alveolar degeneration in mammalian lungs (Massaro and Massaro, 1997),type I diabetes and Schoegren’s syndrome (Miwako and Shudo,2009; Shudo et al., 2009), and Crohn’s disease (Osanai et al.,2007; Shudo et al., 2009).Aging, a major risk factor and oxidative stress, a crucial patho-physiological mechanism have long been implicated in neurode-generative diseases such as AD, Parkinson’s disease, Huntington’sdisease and amyotrophic lateral sclerosis (Polidori, 2003; Beal,1995; Polidori et al., 1999). Mounting evidence suggests thataggravated aging processes such as progeria and Werner syn-dromes intervene with the pathophysiology of neurodegenerativediseases, especially AD via oxidative damage (Polidori, 2003).Increased levels of the xanthophylls, lutein and  b -cryptoxanthinconsiderably decrease levels of lymphocyte 8-hydroxy-2 0 -deoxy-guanosine (8-OHdG) and of urinary 8-epiprostaglandin F 2 a . More-over, supplementation with xanthophylls and lycopene furtherdecreases these biochemical markers of oxidation (Mecocci et al.,2002; Haegele et al., 2000).  b -Carotene also has been shown toabate H 2 O 2  induced oxidative damage to DNA of lymphocytes(Torbergsen and Collins, 2000; Mecocci et al., 2002).The glial glutamatetransporter EAAT2which has beenfound tobe decreased in AD can be regulated at translational level. StudiesinaprimaryastrocytelinethatregularlyexpressedanEAAT2tran-script demonstrated that translation of this transcript can be regu-lated by manifold extracellular factors such as corticosterone andretinol (Tian et al., 2007). Several lines of evidence suggest that 0197-0186/$ - see front matter   2011 Elsevier B.V. All rights reserved.doi:10.1016/j.neuint.2011.04.004 ⇑ Corresponding author. Tel.: +91 9480771061. E-mail address:  mobulesu@gmail.com (M. Obulesu).Neurochemistry International 59 (2011) 535–541 Contents lists available at ScienceDirect Neurochemistry International journal homepage: www.elsevier.com/locate/nci  deficiency of vitamins A and E and  b -carotene is an implication forAD and vascular dementia (Foy et al., 1999; Zaman et al., 1992). Ithasalsobeenshownthatplantextractsshowexemplaryneuropro-tective effects against AD (Obulesu and Rao, 2011). Althoughcarotenoids play a pivotal role in the amelioration of AD symp-toms, yet a few studies showed that increased levels of carotenesmay lead to AD (Sukhdev et al., 1988). 2. Retinoids  2.1. Physiology Studies employing in vitro peroxidation system corroboratedthe antioxidant activities of retinoids in an increasing order as ret-inol>retinal>retinyl palmitate>retinoic acid (Das, 1989; Leeet al., 2009). RA binds to nuclear retinoic acid receptors (RARs)and retinoid X receptors (RXRs) (Mangelsdorf and Evans, 1995)thus involving in crucial biological processes such as proliferation,differentiation, and apoptosis (Ueki et al., 2008; Tsai et al., 2009;Lee et al., 2009). Despite the probable role of RA-instigated releaseof arachidonic acid and its metabolites in cell proliferation, differ-entiation, and apoptosis, the underlying molecular mechanism iselusive (Farooqui et al., 2004; Lee et al., 2009). RA provokes phos-pholipase A2 (PLA2), which in turn produces arachidonic acid andits metabolites in the nucleus. Despite the essential role of thesemetabolitesinregulationoffundamentalprocessessuchasneuriteoutgrowth, neurotransmitter release and long-term potentiation(Fig. 1), their increased generation under pathological situationsleads to oxidative stress, inflammation, and neurodegeneration(Farooqui et al., 1997a,b, 2000; Farooqui and Horrocks, 2001; Leeet al., 2009). Numerous genes of proteins that are associated withAD pathology, like choline acetyltransferase (ChAT), insulindegrading enzyme (IDE), or apolipoprotein E (ApoE), are retinoidregulated (Cedazo-Minguez et al., 2001; Kobayashi et al., 1994;Melino et al., 1996; Tippmann et al., 2009).  2.2. Pathology Current AD research focuses on regeneration of degeneratedneural cells by retinoids since it is adequately understood (Shudoet al., 2009; Maden and Hind, 2003; Maden, 2007). It has beenfound that there is a potential link between the availability of RAin the brain and late onset Alzheimer’s Disease (LOAD) (Goodmanand Pardee, 2003). Coexistence of AD loci and retinoid-relatedgenes potentiates retinoids’ involvement in the disease (Goodmanand pardee, 2003). The activity of the RA-producing enzyme reti-naldehydedehydrogenase(RALDH)isaugmentedinthehippocam-pus and parietal cortex in AD brains (Connor and Sidell, 1997;Tippmannet al., 2009). Althoughdistributionof RAwithinthema-ture human central nervous system is incompletely understood(Connor and Sidell, 1997), yet alteration of retinoid transport andindirect evidence supporting reduced concentration of RA in theAlzheimer’s brain has been established (Goodman and Pardee,2003). Growing body of evidence potentiates the involvement of retinoid defective signaling in the pathology of LOAD (Shudoet al., 2009; Goodman and Pardee, 2003; Goodman, 2006) (Fig. 2). RA which acts as an activator of the  a -secretase, activelyameliorates ADAM10 mRNA levels and the ADAM10 promoteractivities, thus substantiating a promising therapeutic avenue(Shudo et al., 2009; Prinzen et al., 2005; Fahrenholz and Postina,2006; Fahrenholz, 2007).Accumulatingevidencesuggeststhatsubstantialsuppressionof IL6 production by retinoids, make them amenable treatment op-tion for AD (Shudo et al., 2009; Zitnik et al., 1994; Kagechikaetal., 1997). IthasalsobeenshownthatRAwhichplaysasubstan-tial role in supporting integrity of olfactory system (Rawson andLaMantia, 2006, 2007) can ameliorate AD symptoms induced byolfactory dysfunction (Doty, 2008; Ross et al., 2008; Tabert et al.,2005). Despite the availability of adequate evidence for theinvolvement of impaired RA signaling in AD, the molecular under-pinningsof this processinthebrainare yet tobeunderstood(TaftiandGhyselinck, 2007). RAhas beenfoundtoplaya roleinamyloidplaque formation since the wealth of in vitro studies (Tafti andGhyselinck, 2007; Flood et al., 2004; Konig et al., 1990) showedits involvement in differentiation of neuroblastoma cells, whicheventually up regulates presenilin 1 and 2 and induces amyloidprotein precursor messenger RNA. Several lines of evidence impli-cateretinoidsignalinginAD(TaftiandGhyselinck,2007;Goodman Retinoids Cell Proliferation, differentiation, and apoptosis PHYSIOLOGY RAATRAprovokes PLA2release of arachidonic acidneurite outgrowth, neurotransmitter release. Long-term potentiationOxidative Stress, inflammation, neurodegeneration Synthesized by retinol in cortex, amygdala, hypothalamus, hippocampus, striatum and associated brain regions PATHOLOGY Fig. 1.  Physiology and pathology of RA and ATRA. Fig. 2.  Pathology and therapeutic avenues of retinoids.536  M. Obulesu et al./Neurochemistry International 59 (2011) 535–541  and Pardee, 2003) due to the substantial link between LOAD andchromosomes 10q23 and 12q13, which contain genes involved inRA signal transduction, including,  Rarg   (Tafti and Ghyselinck,2007; Myers and Goate, 2001).  2.3. Treatment  RA shows neuroprotection by curtailing mitochondrial oxida-tive damage, which is a paramount pathological factor of AD (Leeetal., 2009;ObulesuandRao, 2010a; Zhuetal., 2006). RAhasbeen found to be actively involved in the regulation of genes related toAPP processing via its nuclear receptors: the RA receptors (RARs)and retinoid X receptors (RXRs) (Mangelsdorf and Evans, 1995;Lahiri et al., 1995; Yang et al., 1998; Hong et al., 1999; Culvenoret al., 2000; Satoh and Kuroda, 2000; Ding et al., 2008). Panoplyof data suggest that mechanisms involved in the synthesis, trans-port, or function of retinoid are substantial targets for the treat-ment of AD (Goodman, 2006; Tafti et al., 2007; Lee et al., 2009).RA mediates the expression of some AD-related genes in the brainlike b -secretaseenzyme(BACE)(SatohandKuroda,2000;Leeetal.,2009), and A b PP (Hung et al., 1992; Pan et al., 1993; Murray andIgwe, 2003; Yang et al., 1998), presenilin 1 (PS1) and presenilin 2(PS2), which have been found to be involved in the production of A b  (Hong et al., 1999; Lee et al., 2009).It has been reported that RA exerts protective effect on embry-onic neurons against oxidative damage and apoptosis by circum-venting the glutathione reduction (Ahlemeyer and Krieglstein,2000; Lee et al., 2009) (Fig. 2). It also deteriorates staurosporine- induced oxidative stress and apoptosis by restoring the levels of Cu, Zn-superoxide dismutase (SOD-1) and Mn-superoxide dismu-tase (SOD-2) in primary hippocampal cultures (Ahlemeyer et al.,2001; Lee et al., 2009) and aids nerve growth factor-inducedprotection in chick embryonic neurons at 10nM concentration(Ahlemeyer et al., 2000; Lee et al., 2009).Retinoic acid receptor (RAR)  a  signalling in vitro can avert bothintracellular and extracellular A b  accumulation. RAR   a  signallingenhances the expression of a disintegrin and metalloprotease 10,an  a -secretase that processes the amyloid precursor protein intothe non-amyloidic pathway, thus deteriorating A b  production( Jarvis et al., 2010). Neuroprotective action of RAR   a  agonists hasbeen corroborated in both A b -treated cortical cultures andTg2576mousemodel( Jarvisetal.,2010).Conversely,neitherRAR  b nor  c -agonists influence A b  production or A b -induced neuronalcell death ( Jarvis et al., 2010). In line with this (RAR)  a  tangiblyopen a new therapeutic avenue for AD ( Jarvis et al., 2010).  2.4. Vitamin A Wealth of studies accentuated that vitamin A can combat theoxidative stress associated with AD ( Jama et al., 1996; Perriget al., 1997; Lee et al., 2009). Studies in AD patients demonstratedabated serum concentrations of vitamins A, C, E and  b -carotene(Foy et al., 1999; Jimenez-Jimenez et al., 1997, 1999; Lee et al.,2009; Riviere et al., 1998; Zaman et al., 1992). Epidemiologic stud- iesaccentuatedthatdietaryintakeof naturalor syntheticproductswith antioxidant effect, such as vitamin E, ameliorates AD symp-toms(Grant,1999;Leeetal.,2009;Smithetal.,1999)(Fig.2).Vita- min A and retinoids being redox-active molecules, can act asantioxidant at low concentration or pro-oxidants at augmentedvitamin concentrations (Lee et al., 2009; Mantymaa et al., 2000;Zanotto-Filho et al., 2008).  2.5. Animal models It has also been shown that RA has the potential to ameliorateimpaired retinoid signaling pathway and ChAT expression in adultrats caused by dietary deficiency of vitamin A (Shudo et al., 2009;Husson et al., 2006; Corcoran et al., 2004). Vitamin A shows anexemplary antiamyloidogenic activity through its antioxidantactivity in vitro (Tafti and Ghyselinck, 2007; Ono et al., 2004). Thisfinding has also been substantiated by an observation that ratswith vitamin A deficiency show burgeoning amyloid  b  depositionin their cortex (Tafti and Ghyselinck, 2007; Corcoran et al., 2004),and the RA treatment can reverse this effect (Tafti and Ghyselinck,2007; Husson et al., 2006). It also results in major neuropathologi-cal events like loss of hippocampal long-termpotentiation(Misneret al., 2001), and memory deficits in rodents (Cocco et al., 2002; Etchamendy et al., 2003, 2001; Ding et al., 2008). In accordance with these findings decreased levels of Vitamin A in the blood(TaftiandGhyselinck,2007;Rinaldietal.,2003)andreducedlevelsof RA-synthesizing enzyme retinaldehyde dehydrogenase 2 in thecortex and meningeal vessels of postmortem AD brains have beenfound (Tafti and Ghyselinck, 2007; Corcoran et al., 2004). 3. All trans retinoic acid  3.1. Physiology Retinol absorbed by cells gets converted to ATRA in the cyto-plasm (Sandell et al., 2007; Lee et al., 2009). Although RA existsin many stereoisomeric forms yet mostly it exists as ATRA (Leeet al., 2009). Elements of the retinoid metabolic pathway foundin adult brain tissues, accentuate that ATRA can be synthesizedin distinct regions of the adult brain such as the cortex, amygdala,hypothalamus, hippocampus, striatum and associated brain re-gions(Kaneetal.,2008;Leeetal.,2009)(Fig.1).ATRAbeingalipo- philic molecule can traverse easily through the cellular membraneunlike other isoforms like 13-cis RA probably due to its amenableconfigurations (Le Doze et al., 2000; Lee et al., 2009).  3.2. Treatment  Since the neuro-inflammation is one of the factors entailed inADetiology, ATRAmayalso playaninhibitoryeffect on ADpathol-ogy (Lee et al., 2009). ATRA being a predominant anti-mitotic anddifferentiation-inducing agent, may inhibit A b PP processing andtau hyperphosphorylation by suppressing the cell cycle proteins(Lee et al., 2009). Since the ATRA has the ability to curb cell cycleand instigate apoptosis, RA can act as a proapoptotic agent in neo-plastic and developing cells (Herget et al., 1998; Lee et al., 2009;Zhengetal.,1997)(Fig.2).ATRAmediatesthelevelsofA b  peptidesby enhancing  a -secretase expression and activity. Furthermore,ATRA treatment modifies the localization of BACE1 and PS1 toattenuate A b PP cleavage (Koryakina et al., 2009; Lee et al., 2009).ATRA also deteriorates formation of fibrillar A b  from fresh A b (Ono et al., 2004), accentuating its involvement in manifold stepsof A b  deposition. There is also a possibility of deterioration of p35levelsbyATRA,thusweakeningA b depositionthroughthereg-ulation of axonal transport of A b  (Ding et al., 2008). Despite theinvolvement of both Cyclin dependent kinase 5 (CDK5) and glyco-gensynthasekinase3 b  (GSK3 b ) intheregulationof tauphosphor-ylation in the brain (Lovestone and Reynolds, 1997), a few studieshave shown that ATRA attenuates the tau phosphorylation viaCDK5inhibitioninsteadofGSK3 b .Thisisbecauseofthevulnerabil-ity of CDK5 phosphorylation sites to the ATRA unlike GSK3 b  (Dingetal., 2008). AlthoughGSK3 b  phosphorylationsitesarenotvulner-able to ATRA treatment, yet a few selected sites, e.g., Ser235,Ser396, Ser404, Ser519, and Thr205, the phosphorylation of tauat Ser396, which are catalyzed by GSK3 b  instead of CDK5 (Li andPaudel, 2006; Wang et al., 2007), show mild attenuation to theATRA treatment (Ding et al., 2008). Since CDK plays a vital role in M. Obulesu et al./Neurochemistry International 59 (2011) 535–541  537  APPphosphorylationinneuronalcells(Iijimaetal., 2000;Liuetal.,2003; Wen et al., 2008), ATRA’s protective action against A b  depo-sition can be via suppression of CDK (Ding et al., 2008).  3.3. Animal models Administration of ATRA to the 5month old APP and PS1 doubletransgenic mice for 8weeks provokes reduction of A b  accumula-tion and tau hyperphosphorylation (Moolman et al., 2004;Trinchese et al., 2004; Zhang et al., 2005; Ding et al., 2008). A b being a potential activator of microglia and astrocytes seen in ADbrain(Rozemulleretal.,2005)andinADanimalmodels(Frautschy et al., 1998; Apelt and Schliebs, 2001; Matsuoka et al., 2001), itsinhibitionbyATRAmayleadtoconsiderablereductioninactivatedmicroglia and astrocytes in APP/PS1 mice (Ding et al., 2008). Theneuroprotective effect of ATRAobservedinAPP/PS1miceis closelyassociated with a study demonstrating its defensive role againstA b -induced injury of primary hippocampal neuronal cultures(Sahin et al., 2005). Since ATRA substantially circumvents thereduction in ChAT induced by A b  peptides (Sahin et al., 2005), itmay open a possible therapeutic avenue for AD by restoring ChATlevels (Ding et al., 2008). Intracerebral injection of acetretin, asynthetic retinoid, enhancedAPPs a /APPs b  ratio of    40%in corticaltissue samples of APP/PS1–21 double transgenic mice (Tippmannet al., 2009). Additionally, introduction of a synthetic retinoidresulted in reduction of A b 42 by   50% and A b 40 by   25% in mice(Tippmann et al., 2009). 4. Antioxidant micronutrients Antioxidant micronutrients are small molecular weight com-pounds like ascorbate (vitamin C),  a -tocopherol (vitamin E) andcarotenoids, provided to the organism through the diet – particu-larlybyfruitsandvegetablesplayacrucialroleinscavengingreac-tive oxygen species, reactive nitrogen species which usuallygenerate oxidative stress in turn intervening with age related dis-eases like AD (Polidori, 2003; Obulesu et al., 2011a; Rowley et al.,2001; Brouwer et al., 1999) (Fig. 2). Afewstudies have shown that low levels of antioxidant micronutrients found during aging, sub-stantially contribute to oxidative stress-related diseases (Polidori,2003; Butterfield et al., 2001; Sies et al., 2003). Inverse relationbe-tween plasma levels of lutein, lycopene,  a - and  b -carotene, to thelymphocyte DNA content of an oxidized base, 8-OHdG, in AD pa-tients (Polidori, 2003; Mecocci et al., 2002) and lycopene’s protec-tive effects against oxidative damage, make this as an amenabletreatment option either to prevent or slow the progression of AD(Polidori, 2003; Riso et al., 2003). It has also been shown that xan-thophylls and lycopene have an exemplary potential to scavengebiomarkers of DNA and lipid oxidation in humans (Polidori,2003; Haegele et al., 2000). Augmented intake of foods enrichedwith vitamin E but not vitamin C, beta carotene, or flavonoids,maymoderatelycurtaillong-termriskofdementiaandAD(Devoreet al., 2010). Despite the failure of clinical trials to show ameliora-tion of AD symptoms through antioxidant supplements (Petersenetal., 2005;Sanoetal.,1997;Devoreetal.,2010)thewidervarietyof antioxidants in food sources and their mechanisms relative todementia risk are yet to be unraveled. A few studies, (Commengeset al., 2000; Morris et al., 2002; Engelhart et al., 2002; Luchsingeret al., 2003; Devore et al., 2010) with varying lengths of follow-up, have failed to show consistent results (Devore et al., 2010). 5. Lycopene Wealth of studies substantiated that lycopene found in toma-toes(Risoetal.,1999)demonstratesidealprotectiveeffectsagainstoxidative DNA damage (Obulesu et al., 2009; Obulesu and Rao,2010a), either by decreasing DNA strand breaks (Haegele et al.,2000) or by increasing DNA resistance to hydrogen peroxide(H 2 O 2 )-induced oxidation (Mecocci et al., 2002) (Fig. 2). Lycopene is a substantial antioxidant compared to  b -carotene in scavengingsingletoxygen(Polidori, 2003;Di Mascioetal., 1989). Alargebodyof experimental evidence proposes that the relationship betweenlymphocyte DNA 8-OHdG content and plasma levels of lycopene,lutein,  a -carotene, and  b -carotene, is indirectly proportional(Mecocci et al., 2002). 6. Conclusion Antioxidant micronutrients which include carotenoids exertbeneficialeffectsinthepreventionofseveraloxidativestressbaseddiseases. Although there has been a suspicion whether oxidativestress is a consequence or a causative step in the development of neurodegenerative processes yet there is a growing need tostreamline substantial strategies to combat this. Adequate con-sumption of fruits and vegetables can potentiate the plasma anti-oxidant capacity in humans (Polidori, 2003; Weisburger, 2002).Furthermore, substantial nutritional supplements enhance plasmalevels of carotenoids, vitamins (Ames, 1998) and antioxidants(Broekmans et al., 2000). Despite the number of studies on RA’srole in decreasing A b -associated neurodegeneration and AD pre-vention, there has been a substantial dearth of AD animal modelsto show a therapeutic effect of RA on AD (Ding et al., 2008;Goodman and Pardee, 2003; Goodman, 2006; Maden, 2007). Addi-tionally, the mechanisms underlying the inhibitory role of ATRAinCDK5activity are yet to be understood(Ding et al., 2008). Thepro-tectiverole of carotenoids against degenerativeconditions, suchascancer and coronary heart disease, is yet to be understood(Mecocci et al., 2002; Halliwell, 1996; Cooper et al., 1999). 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