vitamin a and alzheimer's disease

REVIEW ARTICLE

Vitamin A and Alzheimer’sdiseaseggi_786 180..188

Kenjiro Ono and Masahito Yamada

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School ofMedical Science, Kanazawa, Japan

The deposition of amyloid b-protein (Ab) in the brain is an invariant feature of Alzheimer’sdisease (AD). Vitamin A, which has been traditionally considered an anti-oxidant com-pound, plays a role in maintaining higher function in the central nervous system. Plasmaor cerebrospinal fluid concentrations of vitamin A and b-carotene have been reported to belower in AD patients, and these vitamins have been clinically shown to slow the progres-sion of dementia. Vitamin A (retinol, retinal and retinoic acid) and b-carotene have beenshown in in vitro studies to inhibit the formation, extension and destabilizing effects ofb-amyloid fibrils. Recently, the inhibition of the oligomerization of Ab has been suggestedas a possible therapeutic target for the treatment of AD. We have recently shown theinhibitory effects of vitamin A and b-carotene on the oligomerization of Ab40 and Ab42in vitro. In previous in vivo studies, intraperitoneal injections of vitamin A decreased brainAb deposition and tau phosphorylation in transgenic mouse models of AD, attenuatedneuronal degeneration, and improved spatial learning and memory. Thus, vitamin Aand b-carotene could be key molecules for the prevention and therapy of AD. GeriatrGerontol Int 2012; 12: 180–188.

Keywords: Alzheimer’s disease, amyloid b-protein, oligomer, vitamin A.

Introduction

Alzheimer’s disease (AD), which is a progressive neuro-degenerative disorder, is characterized by cerebral depo-sitions in the form of extracellular amyloid plaques andintracellular neurofibrillary tangles.1 Amyloid plaquesconsist of an insoluble, aggregated core of amyloidb-protein (Ab) that is surrounded by dystrophic axons,dendrites, activated microglia and reactive astrocytes.1

Neurofibrillary tangles are composed of hyperphospho-rylated tau protein that destroys cellular architectureand aggregates into paired helical filaments in the cyto-plasm of limbic and cortical neurons.1

Limited numbers of drugs are available for ADtherapy, most of which are acetylcholine esterase inhibi-

tors or uncompetitive antagonists of the N-methyl-D-aspartate receptor.2–4 These drugs improve neuraltransmission, but do not modify the disease process.Many researchers favor therapeutic approaches thattarget the production, aggregation, deposition and clear-ance of Ab. They include Ab immunotherapies,5–10

b- or g-secretase inhibitors11–14 and anti-inflammatorydrugs;15–19 the use of these drugs has been reported inexperimental studies, as well as in clinical trials.

The aggregation of Ab has been considered as a criti-cal step in the pathogenesis of AD. The most potentneurotoxic assemblies appear to be oligomeric ratherthan fibrillar in nature.20,21

Vitamin A, which is synthesized by the centralnervous system (CNS) more than by any other organ,regulates a number of genes that are expressed in theCNS. In addition, it plays important roles in the devel-opment of the CNS.22–24 Vitamin A, which has beentraditionally considered to be an anti-oxidant com-pound, plays a role in maintaining higher CNS func-tions in older subjects.25 AD patients have been reportedto have low serum and plasma concentrations ofvitamin A and b-carotene.26–30 It has been reported that,among 442 patients (aged 65–94 years), a higher plasma

Accepted for publication 31 October 2011.

Correspondence: Dr Kenjiro Ono MD PhD, Department ofNeurology and Neurobiology of Aging, Kanazawa UniversityGraduate School of Medical Science, 13-1 Takara-Machi,Kanazawa 920-8640, Japan. Email: [email protected]

This article was awarded the Novartis Prize by the JapanGeriatric Society.

Geriatr Gerontol Int 2012; 12: 180–188

180 � © 2011 Japan Geriatrics Societydoi: 10.1111/j.1447-0594.2011.00786.x

concentration of b-carotene was associated with bettermemory performance.31 In addition, a cross-sectionalstudy that was carried out in the Netherlands showedthat a higher intake of b-carotene was associated withbetter cognitive performance in older subjects.32

Previously, we reported that vitamin A and b-carotenedose-dependently inhibited the formation of b-amyloidfibrils (fAb) from fresh Ab, and also dose-dependentlydestabilized preformed fAb in vitro.33 Recently, weshowed the inhibitory effects of vitamin A andb-carotene on the oligomerization of Ab40 and Ab42in vitro.34 In the present review, we have summarizedrecent studies of Ab aggregation, and the effect ofvitamin A and b-carotene on this aggregation, and havediscussed the potentials of these compounds as candi-dates for preventive and therapeutic agents for AD.

Ab aggregation is a therapeutictarget of AD

Ab was purified from the meningeal vessels andsenile plaques of AD patients and individuals with Downsyndrome.35,36 The subsequent cloning of the b-amyloidprecursor protein (APP) gene, and its localization tochromosome 21,37–39 coupled with the fact that Downsyndrome (trisomy 21) invariably leads to the neuropa-thology of AD,40 led to the hypothesis that Ab accumu-lation is the primary event in AD pathogenesis. Inaddition, presenilin-1 (PS1) and presenilin-2 genes41–43

that contributed to enhancing APP processing44,45 wereidentified in familial AD. These facts support the notionthat aberrant APP metabolism is a key feature of AD.Thus, genetic and pathological evidence strongly sup-ports the amyloid cascade hypothesis, which suggeststhat the accumulation of Ab in the brain is the firstpathological event that leads to AD (Fig. 1). The Ab thatis deposited in the brain consists of two major species,Ab40 and Ab42, which differ depending on whether theC terminus of Ab ends at the 40th or 42nd amino acid,respectively.46–48 In the brains of AD patients, Ab42 is thepredominant species that is deposited in the brain paren-chyma.49 Further experimental studies have shown thatAb42 is more toxic and aggregates more easily thanAb40,1,50 and Ab42 is essential for amyloid deposition inthe parenchyma and vasculature.51

Recent studies have shown that Ab aggregation and,in particular, its oligomerization, initiates a slow, butdeadly, cascade that leads to synaptic alterations, micro-glial and astrocytic activation, modification of the nor-mally soluble tau protein into oligomers and then intoinsoluble paired helical filaments, progressive neuronalloss that is associated with multiple neurotransmitterdeficiencies, and cognitive failure.1,20,21,52,53

Ab neurotoxicity is mediated by various mechanismsthat range from direct neurotoxic interactions withthe neuronal membrane to Ab’s effects on membrane

receptors and intracellular signaling.54 Interestingly, itwas found that Ab, in order to exert its toxic activities,needs to be aggregated and that it directly interactswith the cell membrane in the aggregated form.54 It wasproposed that this interaction is not random, but israther mediated by the receptor for advanced glycationend-products.55 Recent studies have shown that thedegree of neurotoxicity can be demonstrated with theamount of prefibrillar Ab aggregates, especially that ofAb oligomers.20,21,52,53

Furthermore, Ab aggregates on the nerve cellmembrane have been reported to induce a sequence ofevents that lead to the intracellular accumulation ofreactive oxygen species.56 Micromolar concentrationsof Ab cause oxidation of the non-saturated carbohy-drate side-chains of membrane lipids, disintegrationof the neuronal membrane, and, subsequently,cell lysis.56 A variety of additional studies thatwere carried out by different laboratories supported theview that oxidative stress might be central to Ab-drivenneurodegeneration.54

In vitro studies on Ab aggregation

A nucleation-dependent polymerization model couldexplain the mechanisms of fAb formation in vitro(Fig. 2).57–60 This model consists of two phases; that is,nucleation and extension. Nucleus formation requires a

Degradation

-Secretase

-Secretase

-Secretase

APP

A

A oligomer

A fibrils

Oligomerization

AggregationNeurotoxic

Degradation

Figure 1 Amyloid cascade hypothesis. Cerebral amyloidb-protein (Ab) accumulation is the primary factor inAlzheimer’s disease. APP, b-amyloid precursor protein.

Vitamin A and Alzheimer’s disease

© 2011 Japan Geriatrics Society � 181

series of association steps of monomers that are ther-modynamically unfavorable, representing the rate-limiting step in amyloid fibril formation. Once thenucleus has been formed, the further addition of mono-mers becomes thermodynamically favorable, resultingin the rapid extension of amyloid fibrils according to thefirst-order kinetic model of fAb extension; that is, bythe consecutive association of Ab onto the end ofexisting fibrils.58,61,62 Although this model is based onthe assumption that Ab is monomeric in the reactionmixture, the non-fibrillar Ab intermediates, protofibrilssuggested by Walsh et al.63,64 and Hartley et al.65 wouldalso be consistent with this model.

Recent studies of Ab oligomers have focused onsmaller soluble oligomers, as well as sought to corre-late oligomer size and biological activity.21,53 Chinesehamster ovarian cells that express mutant (V717F)human APP (7PA2 cells) can produce and secrete low-noligomers, and these mainly include dimers, trimers,and occasionally, tetramers.66,67 Walsh et al.67 reportedthat the microinjection of small volumes of these low-noligomers into the lateral ventricle of the brain ofan anesthetized rat inhibited hippocampal long-termpotentiation (LTP) in vivo. In addition, they have shownthat the blockage of LTP was especially mediated bylow-n oligomers and not by monomers or any largeraggregates.68 Townsend et al.69 found that Ab trimersfully inhibited LTP, whereas dimers and tetramers hadan intermediate potency. Low-n oligomers that wereextracted directly from the cerebral cortex of ADpatients potently inhibited LTP, enhanced long-termdepression (LTD) and reduced dendritic spine densityin normal rodent hippocampus.70 These oligomers also

disrupted the memory of learning behavior in normalrats. Insoluble amyloid plaque cores from AD cortex didnot impair LTP unless they were first solubilized inorder to release the Ab dimers, suggesting that plaquecores are largely inactive, but sequester Ab dimers aresynaptotoxic. The Ab dimers extracted from human ADbrain facilitated electrically evoked LTD by disruptingneuronal glutamate uptake in the CA1 region of thehippocampus.71 Recently, we have succeeded in extract-ing low-n Ab oligomers that were stabilized structurallyby using photo-induced cross-linking of unmodifiedproteins (PICUP) and then determined their conforma-tions and neurotoxic activities. We found by circulardichroism spectroscopy that Ab monomers are largelyunstructured, but oligomers show order-dependentincreases in b-sheet content.72 These increases corre-lated with the abilities of the oligomers to nucleate fibrilassembly as well as their cytotoxicity.72 In the cytotox-icity assay, dimers, trimers and tetramers were all sig-nificantly more toxic than monomers.72

Although low-n oligomers of Ab are presumed tocause synaptic cognitive dysfunction in AD, their con-tribution to other pathological features of AD remainsunclear. To determine the interaction of Ab oligomerswith tau pathology, Oddo et al.73 used 3xTg-AD mice,which develop a progressive accumulation of Abplaques and tangles, and have cognitive impairments.They presented evidence that the formation of sodiumdodecyl sulfate (SDS)-resistant low-n oligomers ofAb, including dimers, trimers and pentamers, firstoccurs intraneuronally. They have also shown that asingle intrahippocampal injection of a specific oligomerantibody is sufficient to treat Ab pathology, and moreimportantly, tau pathology.73 These findings suggestthat low-n oligomers of Ab cause not only synapticalterations, but also other features of AD pathology.

It has recently been reported that the prion protein(PrP) can function as a cellular receptor for the Abaggregates that are referred to as Ab-derived diffusibleligands (ADDL) and that PrP is required for the disrup-tion of synaptic plasticity that is mediated by ADDL.74 Ananomolar affinity of binding75–77 and blocking by asingle anti-PrP monoclonal antibody with an epitopearound residues 95–105 of ADDL binding and toxicity74

have been reported. In further studies, an antibody tothe helix-1 of PrP was shown to prevent ADDL bindingto PrP, as well as to block the disruption of synapticplasticity that is mediated by both ADDL and ADbrain-derived Ab.78

In vitro effects of vitamin A onAb aggregation

We first examined the effects of anti-oxidant vitaminsand their analogs, such as vitamin A (retinol, retinal andretinoic acid), b-carotene, and vitamins B2, B6, C and E

+

1) Nucleation phase

2) Extension phase

A monomer Nucleus

fA (n-polymer) A monomer fA (n+1 polymer)

Kon

Koff

Figure 2 Schema of the nucleation-dependentpolymerization model. Ab, amyloid b-protein; fAb, b-amyloidfibrils; Koff, the dissociation rate constants; Kon, theassociation rate constants.

K Ono and M Yamada

182 � © 2011 Japan Geriatrics Society

on the formation, extension, and destabilization of fAbusing fluorescence spectroscopy with thioflavin T andelectron microscopy in vitro. Among them, vitamin Aand b-carotene dose-dependently inhibited the forma-tion of fAb from fresh Ab, as well as their extension.33

Furthermore, they dose-dependently destabilized pre-formed fAb. Destabilized fAb was less toxic than intactfAb.33 The anti-amyloidogenic and fibril-destabilizingactivities of vitamin A and b-carotene were in the fol-lowing order: retinol = retinal > b-carotene > retinoicacid.33 Recently, we showed that vitamin A and b-carotene dose-dependently inhibited the oligomeriza-tion of Ab40 and Ab42, whereas vitamin B2, B6, C, E,coenzyme Q10 and a-lipoic acid had no inhibitoryeffects on the oligomerization using PICUP, SDS-polyacrylamide gel electrophoresis, electron microscopyand atomic force microscopy (Figs 3,4).34 Furthermore,vitamin A decreased cellular toxicity by the inhibitionof Ab42 oligomerization (Fig. 5).34 The anti-oligomericactivities of vitamin A and b-carotene were in thefollowing order: retinoic acid > retinol = retinal > b-carotene.34 In the Ab40 system, the effective concentra-tion (EC50) of retinoic acid was 61.5 mmol/L. The EC50

of retinol, retinal and b-carotene were 122.3, 115.6and 128.0 mmol/L, respectively. Similarly, in the Ab42system, the EC50 of retinoic acid was 29.4 mmol/L,whereas the EC50 of retinol, retinal and b-carotenewere 46.6, 69.5 and 115.3 mmol/L, respectively. Takentogether with the results of the aforementionedanti-fibrillation and anti-oligomerization experiments,retinol and retinal are more effective in the inhibition offibrillation than of oligomerization. In contrast, retinoicacid is more effective in the inhibition of oligomeriza-tion than of fibrillation. The hydroxyl group of retinol issuccessively converted to an aldehyde group (retinal)and a carboxyl group (retinoic acid). Some interestingstructure–activity relationships can be considered. First,retinol, retinal and b-carotene have no charge underphysiological aqueous conditions, whereas retinoic acidis negatively charged as a result of the terminal carboxylgroup (Fig. 6). Second, the water solubility of retinoicacid, retinol and retinal is in the following order:retinoic acid > retinal > retinol, under physiologicalconditions.79 The negative charge and increase inhydrophilicity might increase the binding affinity of ret-inoic acid to monomer or low-order oligomers andresult in its inhibitory effects on the oligomerization ofAb40 and Ab42 in vitro.

b-carotene has been reported to protect embryonic rathippocampal neurons not only from ethanol alone, butalso from a combination of ethanol and ischemia.80,81

Similarly, it has been reported that retinoic acid pro-tected embryonic neurons from oxidative damageand apoptosis by inhibiting glutathione depletion.82 Ithas been suggested that retinoic acid might play animportant role in protecting hippocampal neurons from

Ab-induced cell death.83 Accordingly, vitamin A andb-carotene might protect neurons against not only oxi-dative stress, but also Ab-induced toxicity.

In vivo effects of vitamin A in ADmodel animals

Deprivation of vitamin A has been reported to result inthe loss of hippocampal LTP,84 memory deficits in

(a)

(b)

A 40

Mr (k

Da)

Vitamin B2

2

Retinoic acid Retinol Retinal -Carotene

66.3

1

55.4

36.531.0

21.5

14.4

6.0

3.5

3 4 5 6 7 8 9 10 11 12 13

A 4266.355.4

36.531.0

21.5

14.4

6.0

3.5

Vitamin B2

2

Retinoic acid Retinol Retinal -Carotene

1 3 4 5 6 7 8 9 10 11 12 13

Mr (k

Da)

Figure 3 (a,b) Amyloid b-protein (Ab) oligomerization and(c,d) the dose-dependent inhibition of Ab oligomerization.Photo-induced cross-linking of unmodified proteins, sodiumdodecyl sulfate-polyacrylamide gel electrophoresis, and silverstaining were used to determine the effects of 25 mmol/L and250 mmol/L of vitamin B2, retinoic acid, retinol, retinal orb-carotene on the oligomerization of (a) Ab40 or (b) Ab42.Lanes 1, molecular weight markers; lanes 2, Ab alone(uncross-linked); lanes 3, Ab alone (cross-linked); lanes 4,Ab with vitamin B2 (25 mmol/L); lanes 5, Ab with vitamin B2(250 mmol/L); lanes 6, Ab with retinoic acid (25 mmol/L);lanes 7, Ab with retinoic acid (250 mmol/L); lanes 8, Ab withretinol (25 mmol/L); lanes 9, Ab with retinol (250 mmol/L);lanes 10, Ab with retinal (25 mmol/L); lanes 11, Ab withretinal (250 mmol/L); lanes 12, Ab with b-carotene (25 mmol/L); and lanes 13, Ab with b-carotene (250 mmol/L). Eachgel is representative of each of the three independentexperiments. This research was originally published in JAlzheimers Dis by Takasaki et al.



Figure 4 Morphological analysis of(a–f) amyloid b-protein (Ab)40 or(g–l) Ab42 assemblies by electronmicroscopy and atomic forcemicroscopy. (a,g) Uncross-linked Ab,(b,h) cross-linked Ab and (c,i)cross-linked Ab with 250 mmol/L ofretinoic acid were examined byelectron microscopy. (d,j) Uncross-linked Ab, (e,k) cross-linked Ab, and(f,l) cross-linked Ab with 250 mmol/Lof retinoic acid were examined byatomic force microscopy. Scale bars,100 nm. This research was originallypublished in J Alzheimers Dis byTakasaki et al.

(d) (e) (f)

(a) (b) (c)

(g) (h) (i)

(j) (k) (l)

A 40

A 42

* *

UnXL

mol/L

v

mol/L mol/L

A 42

XL A 42

XL A 42 + retinoic acid

*

****

Figure 5 Cell viability. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide)assays were carried out on HEK293 cells that were incubatedfor 22 h with uncross-linked Ab42 (UnXL Ab42),cross-linked Ab42 (XL Ab42) and cross-linked Ab42 withretinoic acid (XL Ab42 + retinoic acid) of Ab42 at finalnominal concentrations of 0.1, 1 and 10 mmol/L. Eachcolumn represents means 1 SE (n = 12). Differences reachingstatistical significance are noted by line segments betweensamples, along with their associated P-values, where *signifies P < 0.01. This research was originally published inJ Alzheimers Dis by Takasaki et al.

All-trans retinoic acid

All-trans retinol All-trans retinal

-Carotene

Figure 6 Structures of all-trans retinol, all-trans retinal,all-trans retinoic acid and b-carotene.

K Ono and M Yamada


rodents85,86 and Ab accumulation,87 all of which are thehallmarks of AD. Vitamin A-deprived mice showed aprogressive and ultimately profound impairment of hip-pocampal CA1 LTP and a virtual elimination of LTD.84

Importantly, these losses were fully reversible by dietaryvitamin A replenishment in vivo or the direct applicationof all trans-retinoic acid to acute hippocampal slices.84

Comparing mice fed with a vitamin A-free diet tocontrol groups fed with a control diet, vitamin A defi-ciency resulted in some cognitive deficits, which wereexclusively observed when the expression of neurogra-nin was significantly decreased, and thereby suggestingthat normal cognitive function might critically dependon a sufficient level of expression of certain retinoidtarget genes.86 The deposition of Ab in the cerebralblood vessels of adult rats has been reported 1 year afterthe disruption of the retinoid signaling pathway by thedietary deficiency of vitamin A.87 In addition, there was adownregulation of retinoic acid receptor-a in the fore-brain neurons of retinoid-deficient rats and a loss ofcholine acetyl transferase expression, which precededAb deposition.87 In the neocortex of pathologicalsamples from AD patients, a similar retinoic acidreceptor-a deficit as that in the retinoid-deficient ratswas observed in the surviving neurons.87

Furthermore, a robust decrease in brain Ab deposi-tion and tau phosphorylation was reported in a blindedstudy of APP/PS1 transgenic mice that were treatedintraperitoneally for 8-weeks with retinoic acid.88 Thiswas accompanied by a significant decrease in APP phos-phorylation and processing.88 The retinoic acid-treatedAPP/PS mice showed decreased activation of microgliaand astrocytes, attenuated neuronal degeneration, andimprovements in spatial learning and memory com-pared with vehicle-treated APP/PS mice.88 These resultssupport the hypothesis that retinoic acid might bean effective therapeutic agent for the prevention andtreatment of AD.

Potential of vitamin A as a preventive/therapeutic agent for AD

AD patients have been reported to have low serum andplasma concentrations of vitamin A and b-carotene.26–30

Importantly, the transport and function of retinoic acidwere shown to be defective in the AD brain.89 It hasbeen reported that higher b-carotene plasma levels wereassociated with better memory performance in 442 sub-jects (aged 65–94 years).31 Human plasma concentra-tions of vitamin A and b-carotene are 1.27–2.99 mmol/Land 0.13–1.53 mmol/L, respectively.30 Vitamin A andb-carotene readily cross the blood–brain barrier.90,91 TheEC50 of vitamin A and b-carotene for Ab oligomeriza-tion in our experimental model might have been higherthan their physiological concentrations in the humanbrain. However, vitamin A and b-carotene might show

anti-oligomerization activities in vivo if given with a highdosage over a long period.

Conclusion

Vitamin A and b-carotene have been shown to haveanti-oxidative, cell protective, and anti-aggregation (oli-gomeric) effects in in vitro and in vivo models. Becausevitamin A inhibits the formation of both Ab oligomersand fibrils, these compounds might be key moleculesfor the development of preventive or therapeuticapproaches for AD.

Acknowledgments

This work was supported by a grant for KnowledgeCluster Initiative (High-Tech Sensing and KnowledgeHandling Technology [Brain Technology]) (M.Y.), aGrant-in-Aid for Scientific Research (B) (KAKENHI20390242) (M.Y.) and Grant-in-Aid for Young Scien-tists (B) (K.O.) from the Japanese Ministry of Education,Culture, Sports, Science and Technology, Japan, a grantto the Amyloidosis Research Committee from the Min-istry of Health, Labour, and Welfare, Japan (M.Y andK.O.), a grant from the Novartis Foundation for Ger-ontological Research (K.O.), and a grant from AlumniAssociation of the Department of Medicine at ShowaUniversity (K.O.).

Disclosure statement

We have no conflict of interest.

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