review article vitamin d and alzheimer s disease...

Review ArticleVitamin D and Alzheimerrsquos DiseaseNeurocognition to Therapeutics

Anindita Banerjee12 Vineet Kumar Khemka12 Anirban Ganguly2 Debashree Roy2

Upasana Ganguly2 and Sasanka Chakrabarti1

1Department of Biochemistry ICARE Institute of Medical Sciences and Research Haldia 721645 India2Department of Biochemistry Institute of Post Graduate Medical Education and Research Kolkata 700020 India

Correspondence should be addressed to Anindita Banerjee annybanerjeegmailcom

Received 31 May 2015 Accepted 16 July 2015

Academic Editor Francesco Panza

Copyright copy 2015 Anindita Banerjee et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Alzheimerrsquos disease (AD) the major cause of dementia worldwide is characterized by progressive loss of memory and cognitionThe sporadic form of AD accounts for nearly 90 of the patients developing this diseaseThe last century has witnessed significantresearch to identify various mechanisms and risk factors contributing to the complex etiopathogenesis of AD by analyzingpostmortemAD brains and experimenting with animal and cell culture basedmodels However the treatment strategies as of noware only symptomatic Accumulating evidences suggested a significant association between vitaminDdeficiency dementia andADThis review encompasses the beneficial role of vitamin D in neurocognition and optimal brain health along with epidemiologicalevidence of the high prevalence of hypovitaminosis D among aged and AD population Moreover disrupted signaling alteredutilization of vitamin D and polymorphisms of several related genes including vitamin D receptor (VDR) also predispose to ADor AD-like neurodegeneration This review explores the relationship between this gene-environmental influence and long termvitamin D deficiency as a risk factor for development of sporadic AD along with the role and rationale of therapeutic trials withvitamin D It is therefore urgently warranted to further establish the role of this potentially neuroprotective vitamin in preventingand halting progressive neurodegeneration in AD patients

1 Introduction

Alzheimerrsquos disease (AD) is the most common form ofdementia in the aging population Currently 37 millionpeople around the globe have dementia and the number isexpected to double every 20 years [1 2] AD and AD relateddementia (ADRD) are a global health problem [3] AD isclinically characterized by progressive deficits of memoryand other cognitive functions leading to complete incapacityand death within 3ndash9 years of diagnosis [4] Pathologicalhallmarks of AD include histopathological changes inducedby the extracellular deposition of amyloid 120573 peptides formingsenile plaques (SP) and intracellular neurofibrillary tangle(NFT) of hyperphosphorylated tau proteins in the brain [5]Recent studies have identified that low serum concentrationsof vitamin D can substantially increase the risk of AD [6]In addition to modulating neurite growth proliferation dif-ferentiation and calcium signaling vitamin D has also been

implicated in neuroprotection and may alter neurotrans-mission and synaptic plasticity [7] Brain imaging studieshave linked hypovitaminosis D to dysfunction of the frontal-subcortical neuronal circuits [8] Vitamin D deficiency hasalso been linked with increasing hypertension hyperlipi-demia myocardial infarction and stroke which are also riskfactors for AD [9] This review will focus primarily on thecomplex underlying mechanisms that promote vitamin Ddeficiency as a major contributory factor in the progressionof sporadic AD and analyze its potential as a possibletherapeutic target

2 Pathogenesis of AD

AD is a multifactorial disease and the mechanisms under-lying its pathogenesis are complex Several postmortem

Hindawi Publishing CorporationInternational Journal of Alzheimerrsquos DiseaseVolume 2015 Article ID 192747 11 pageshttpdxdoiorg1011552015192747

2 International Journal of Alzheimerrsquos Disease

evidences studies in transgenic animal models and cell-based models (cell lines and primary cortical neurons) haveimproved our understanding of the pathogenesis of AD [10ndash14] These studies have implicated amyloid 120573 (A120573) accu-mulation hyperphosphorylated tau oxidative stress metaldysregulation mitochondrial dysfunction and inflamma-tory response as major interconnecting networks leadingto neuronal and synaptic degeneration [15ndash18] Alterationsin the amyloid metabolic cascade constitute an importanthypothesis in AD though none of the theories alone issufficient to decipher the biochemical and pathological com-plexities that result in disease progression [19] Corticalplaques in AD brain primarily contain A120573 protein which isproduced from its parent amyloid precursor protein (APP)through sequential hydrolysis by 120573 and 120574-secretases [20]The major species of A120573 are A120573-40 and A120573-42 peptidesand the latter is predominant in neuritic plaques and has ahigher propensity to aggregate and form the characteristictoxic amyloid fibrils in AD [21 22] In spite of evidences insupport of ldquoamyloid cascade hypothesisrdquo and ldquotauopathyrdquo itis still unclear how these events are triggered in the agingbrain and how they contribute to the complexity and the het-erogeneity of AD Moreover it has been established that theetiology of sporadic AD involves multiple gene-environmentinteractions as well as epigenetic mechanisms (as shownin Figure 1) working in the backdrop of aging brain [23]An interesting hypothesis in this regard is the Latent Early-life Associated Regulation (LEARn) model which proposesthat exposure to various environmental risk factors (heavymetals or nutritional deficiency) in the early developmentallife can bring about epigenetic modifications of AD relatedgenes (first hit) which remain latent for many years until asecond hit (aging elevated proinflammatory cytokines anddiet) results in sustained alterations in these genes promotingdisease progression [24]

3 Vitamin D Metabolism

Although vitamin D (calciferol) was discovered in the early20th century as a vitamin it is now recognized as a prohor-mone [25 26] Calciferols are a group of fat soluble secosterolsbroadly divided into twomajor forms ergocalciferol (vitaminD2) and cholecalciferol (vitamin D

3) [27] While vitamin

D2is largely found in food vitamin D

3is synthesized in

the human skin by a photochemical reaction (ultravioletB 297ndash315 nm) from 7-dehydrocholesterol [28] and is alsoconsumed in the diet Vitamin D in either D

2or D3

form is considered biologically inert until it undergoes twoenzymatic hydroxylation reactions First vitamin D bindscarrier proteins in the skin (particularly the vitamin Dbinding protein or DBPs) and is transported to the liver[29] where it is enzymatically hydroxylated by vitamin D-25-hydroxylase (CYP2R) on C-25 thereby generating 25(OH)Dor calcidiol A second hydroxylation reaction in the kidneyby 25(OH) D-1-OHase (CYP27B1) hydroxylates 25(OH)Dat C-1120572 position and converts it to the biologically activeform 125-dihydroxyvitamin D (125(OH)

2D) or calcitriol

[30] 125(OH)2D concentration in the blood is regulated by

a feedback mechanism and by the induction of parathyroidhormone Ca2+ and various cytokines Recent studies haveshown that in addition to renal cells various other cells (ker-atinocytes monocytes macrophages osteoblasts prostateand colon cells) are capable of carrying out the secondhydroxylation reaction [31ndash33] Circulating 25(OH) vitaminD crosses the blood-brain barrier and enters neuronal andglial cells to be converted to 125(OH)

2D [34 35] CYP27B1

has also been detected in developing human fetal brain[36] Recent data has shown that the central nervous systemcan locally perform bioactivation of vitamin D prohormoneand the presence of 1 120572-hydroxylase in human brain Inthis regard it is worth mentioning that microglial cells inculture produce 125(OH)

2D from its precursor [37] The

pattern of distribution of CYP27B1 in human and rat brainsis more or less consistent Previous studies have identified thepresence of another key enzyme CYP24A1 which is involvedin vitamin D catabolism in the human brain and also shownthat CYP24A1 mRNA has been induced by the treatment ofglial cells with 125 OH vitamin D [38] Thus 125(OH)

2D

is produced in various organs and cells functions in anautocrine pathway and leads to its own destruction byactivation of CYP24A1 which hydroxylates and oxidizes it toform the inactive calcitroic acid [30]

Recent evidences link serum vitamin D deficiency tocognitive impairment and dementia [39 40] Vitamin Dreceptors are widely expressed in the brain [41] Expressionof the active form of vitamin D regulates neurotrophinlevels and the survival of neural cells [42] In vitro studiesshow that vitamin D can stimulate the clearance of amyloidplaques by inducing phagocytosis by macrophages and alsoreduces the amyloid-induced cytotoxicity apoptosis andinflammatory responses in primary cortical neurons [43]Thus supplementation with vitamin D may ameliorate thecognitive deficits in the elderly people and control neuronalhealth and homeostasis

4 Vitamin D and Neuroprotection

The effects of vitamin D are exerted through its nuclearhormone receptor vitamin D receptor (VDR) or its mem-brane receptor membrane-associated rapid-response ster-oid-binding protein (125 MARRS) [44] Genomic andnongenomic actions of vitamin D are mediated by nuclearand membrane receptors respectively having identicalreceptor VDR in both locations Classical 125(OH)

2D

genomic signaling which is conducted through the VDRhas structural similarities with the nuclear steroid receptorfamily VDR gene is present on chromosome 12q1311 In 1992with the help of in situ hybridization studies it was proved forthe first time that VDR is expressed in the human brain [45]Expression of VDR mRNA in postmortem brains of patientswith Alzheimerrsquos or Huntingtonrsquos disease was identified usingradiolabeled cDNA probes Human neuroblastoma cell linewas also shown to express VDR [41 46] The presence ofVDR in the astrocytes is indicated by its presence in glialfibrillary acidic protein (GFAP) stained cells in primary rathippocampal cultures [41 47] Secondary oligodendrocyte

International Journal of Alzheimerrsquos Disease 3

Secondary trigger

Environmental andmetabolic risk

factors

Geneticepigenetic modulation

Disturbedneurotrophin and NT

homeostasis

Calcium imbalance

Neuronal hypometabolism

Mitochondrial dysfunction

Oxidative stress

Abnormal protein accumulation

Mechanisms

HyperhomocysteinemiaDiabetesMetal stressHead injuryVitamin D deficiency Psychological stressFolate B12 deficiency Vascular injury

AgingInflammationSedentary

lifestyleNeuronal

degeneration and neuronal

death

Figure 1 Risk factors and pathogenic mechanisms in the aetiopathogenesis of sporadic Alzheimerrsquos disease (AD)

cultures and glial cell-line studies verified this statement [48]The potential role of vitamin D in cellular development anddifferentiation is suggested by its expression in developingbrain [41 49] Bartoccini and colleagues have shown therapidly partitioning of VDR into the lipid richmicrodomainswithin the nuclear membrane in developing hippocampalneurons These microdomains have similar characteristics ofthose found in the plasma membrane [50] Almeras et alhave shown that adult brain functioning can be affected byvitamin D deficiency during development in a rat model[51] Vitamin D regulates transcription of various genes bybinding to nucleus forming a heterodimer with RXR andsubsequently translocating to vitamin D response elementin the DNA [52ndash55] Recent report suggests that VDR iswidely expressed throughout the CNS with the highestexpression in the hippocampus hypothalamus thalamuscortex and subcortex and substantia nigra the areas essentialfor cognition

41 Vitamin D and Regulation of NGF and Neurotransmitters125-Dihydroxyvitamin D [125(OH)

2D] plays a pivotal role

in neuronal differentiation and maturation via control ofthe synthesis of neurotrophic agents such as nerve growthfactor (NGF) and glial cell-line-derived neurotrophic factor(GDNF) neurotrophin 3 and the synthesis of low-affinityp75 NTR receptors [56] Nerve growth factor is importantfor the growth maintenance and survival of certain targetneurons and also has been implicated in maintaining andregulating the normal functioning of the septohippocampal

pathway which is involved in learning and memory Ithas been noted that mature NGF levels are substantiallydecreased in the forebrain of aged animals and patientswith AD In vitro studies using neuronal PC12 cells havesuccessfully shown that APP gene expression is modulatedby NGF and an increase in APP expression is noted uponits withdrawal [57] Calcitriol and vitamin D analogs werereported to enhance NGF induction by increasing AP-1binding activity in the NGF promoter in mouse fibroblasts[58] The genetic expression of numerous neurotransmittersin the brain including acetylcholine dopamine serotoninand 120574-aminobutyric acid is regulated by 125(OH)D and thatis notably in the hippocampus [59ndash61]

42 Vitamin D and Calcium Homeostasis It has been wellknown by the virtue of previous studies that aging brainand also Alzheimerrsquos disease show calcium dysregulationthus coining the term ldquoCa2+ hypothesis of brain aging anddementiardquo [62] The L-type voltage sensitive Ca2+ channelone of the most important proteins in calcium metabolismaging and neurodegeneration is worth mentioning in thiscontext as it is reported that vitamin D regulates intra-neuronal calcium homoeostasis via the regulation of thesechannels including those targeted by A120573 [63 64] Moreoverrapid increase in LVSCC-A1C expression in response to VDRsilencing was found in a study by Gezen-Ak et al whichindicates that chronic inefficiency in vitamin D utilization inbrain renders the neurons vulnerable to neurodegeneration[62 65] Vitamin D treatment leads to downregulation of


LVSCC expression L-type currents and channel density inthe plasma membranes of the hippocampal neurons whichis the possible explanation for the protection of the neuronsfrom calcium excitotoxicity [63]

43 Anti-Inflammatory Role of Vitamin D The potentimmune-modulatory and anti-inflammatory action of vita-min D has long been elicited Age-related inflammatorychanges in the hippocampusmay be reversed by vitaminD asshown in mice models [46] Suppression of proinflammatorycytokines in the brain may be the probable mechanism ofaction for this neuroprotection [66 67] Lipopolysaccharide-induced levels of mRNA encoding macrophage colony-stimulating factor (M-CSF) and tumor necrosis factor 120572(TNF-120572) in cultured astrocytes are partially reduced byvitamin D treatment as shown in few studies [61] Alterationof neurotransmitter synthesis by proinflammatory cytokinessuch as IL-1120573 and IL-6 can have detrimental effect onbehaviour and conditioned learning [67] Calcitriol andits analogs have also been shown to be associated withthe regulation of prostaglandin metabolism and selectiveinhibition of COX-2 activity [68 69]

44 Vitamin D and Amyloid Beta Metabolism Neverthelessit is worth mentioning that vitamin D also regulates theAPP and amyloid beta metabolic aspects The promising roleof 125(OH)

2D in recovering the ability of the macrophages

to phagocytose soluble amyloid 120573 protein came to surfacein a very recent work in macrophages from patients withAlzheimerrsquos disease [43] Another study has shown its abilityto attenuate amyloid 120573 (A120573)42 accumulation by stimulatingphagocytosis of the A120573 peptide [70] and enhancing brain-to-blood A120573 efflux across BBB [71] resulting in decreasednumber of amyloid plaques [72] VDR interacts with SMAD3 which is involved in APP processing through TGF-betasignaling as a transcription factor [73 74]

45 Vitamin D and Brain Oxidative Stress Finally vita-min D was shown to exhibit neuroprotective propertiesagainst glutamate toxicity Cultured rat cortical neuronswere protected from acute glutamate exposure by vitamin Dtreatment through the upregulation of VDR expression andantioxidant effects [75 76] Various reports show that vitaminD exerts its protecting effects against free radicals generatedby reactive species of oxygen and nitric oxide inhibits thesynthesis of inducible nitric oxide synthase and regulates theactivity of the gamma glutamyl transpeptidase which is akey enzyme involved in the metabolism of glutathione [76ndash78] Vitamin D is found in increasing glutathione levels inmesencephalic dopaminergic neurons even after treatmentwith various neurotoxins or inhibitors of glutathione synthe-sis [79] 125(OH)

2D also protects from cerebral endothelial

dysfunction by its inhibitory effects on ROS production andNF-120581B activation Similarly the bEnd 3 cells (mouse brainendothelial cell line) when treated with 125(OH)

2D were

found to be protected from hypoxicoxidative insults Theinhibitory action of vitamin D on I120581B phosphorylation and

P65 translocation to the nucleus accounts for this protectiveeffect [80]

Vitamin D supplementation also enhances brain energyhomeostasis and protein phosphatase 2A (PP2A) activityand modulates the redox state and thus reduces age-relatedtau hyperphosphorylation and cognitive impairment [81]Gene expression in the whole brain and protein expressionin the prefrontal cortex and hippocampus of adult vitaminD-deficient rats has been explored with the help of genearray and proteomics analysis Expression of 74 genes and36 proteins involved in diverse functions such as cytoskele-ton maintenance calcium homeostasis synaptic plasticityand neurotransmission oxidative phosphorylation redoxbalance protein transport chaperoning cell cycle controland posttranslational modifications were significantly alteredin vitamin D deficiency [51 82 83] Moreover vitamin D

2

enriched button mushroom (Agaricus bisporus) is found toimprove memory in both wild type and APPswePSIdE9transgenicmice It is worthmentioning that some very recentstudies have identified the vitamin D binding protein (DBP)a prealbumin interacting with A120573 DBP has been shown toinhibit oligomerization of A120573 in vitro as well as preventingA120573 induced hippocampal synaptic loss and resultingmemoryimpairment [84]

Multiple pathogenic mechanisms implicated in thepathogenesis of sporadic AD and multifaceted neuropro-tective role of 125-dihydroxyvitamin D are summed upabove (Figure 2) In addition to the above mentioned mecha-nisms the protective role of vitamin D in the cardiovascularsystem is exerted through cardiac remodeling endothelialresponse regulation to injury and blood coagulation ulti-mately improving the CNS vascular homeostasis Thus inthis manner vitamin D indirectly protects the brain formcerebrovascular risk factors of AD [85]

5 Evidences Linking Vitamin D DeficiencyNeurocognition and AD

First Llewellyn et al showed an increased risk of losingpoints onMini-Mental State Examination (MMSE) in 6 yearsamong 175 older adults with baseline 25(OH)D 10 ngmLcompared to 157 subjects with 25(OH)D 30 ngmL [86 87]Second Slinin et al followed up the association betweenlower 25(OH)D levels and cognitive decline among agedpopulation (gt65 years) for more than 4 years [87 88]A meta-analysis by Etgen et al highlighted an increasedrisk of cognitive impairment in patients with vitamin Ddeficiency [89] Balion et al compared mean MMSE scoreswith levels of 25(OH)D where he showed a higher averageMMSE score in those participants with higher 25(OH)Dconcentrations [90] Further in the In CHIANTI studyconsisting of 858 adults cognitive decline were associatedwith low concentrations of vitamin D when observed overa period of 6 years [86] Nevertheless the intriguing queryremains the same does hypovitaminosis D contribute tocognitive decline or is it the other way round Deficientsun exposure and feeding difficulties with subsequent fewerintakes of vitamin D-rich foods are predisposed by AD


MARRS

Nongenomic effect

Neurotrophic regulationNGF BDNF regulation

Ache Dopamine synthesis

Calcium homeostasisdarr LVSCC Ca channel

Neuroprotectiondarr glutamate toxicity

darr iNOSdarr NF120581B

uarr glutathione

Amyloid 120573 metabolismuarr A120573 phagocytosis

uarr A120573 efflux across BBBdarr APP promoter activity

Crosstalk

RXR

VDR125 OH

vit D

VDR

VDR

Genomic effects

125 OH

vit D

125 OHvit D

Anti-inflammatory actiondarr proinflammatory

cytokinesdarr COX-2 activity

Figure 2 Mechanisms of 125 OH vitamin D mediated multitargeted neuroprotection in AD VDR vitamin D receptor RXR retinoid Xreceptor MARRS membrane associated rapid response receptors and LVSCC L voltage sensitive calcium channel

disease process itself But this is contradictory to the fact thatin cases with mild AD where major functional disabilitieshave not yet started the association between low 25(OH)Dconcentrations and AD still persists [91] Importantly lon-gitudinal prospective studies have established the temporalrelation between hypovitaminosis D and cognitive disorderswhere older individuals with lower vitamin D levels hada significantly higher risk of global cognitive decline andexecutive dysfunction compared to thosewith normalhighervitamin D levels [86 92 93] Moreover to add to the abovementioned fact studies have reported that low vitamin Dwasassociated with an increased risk of AD [94] More than 50of the prospective studies showed an elevated risk of cognitiveimpairment after 4ndash7 years of follow up in participants withlower 25(OH)D levels when comparedwith participantswithhigher 25(OH)D levels [95] Other cross-sectional studieshave showed increased incidence of vitamin D deficiency inAD patients [87 90]

51 VDR and AD Genome-wide analyses transcriptomicsand proteomics approaches have pointed the role of variousgenes in increasing AD liability for example inflamma-tory genes (IL1 IL6) oxidative stress (NOS) VDR cathep-sin ubiquilin COMT and AChE [96] With VDR being

themajormediator of vitaminDactions recent genome-wideassociation studies have focused on finding the role of VDRpolymorphism in late onset Alzheimerrsquos disease (LOAD)susceptibility [97] A decreased level of VDRmRNAhas beenreported in hippocampal region by analyzing postmortemAD brain [45]

Alteration in receptors VDR and 125-MARRS (mem-brane associated rapid response steroid-binding) genesrelated to the action and metabolism of vitamin D resultin inefficient utilization of vitamin D making neuronsvulnerable to neurodegenerative changes [64 65 97ndash100]Association between AD and polymorphisms of VDR andmegalin strongly supports this notion and therefore explainsthe neurotoxic effects of VDR and 125-MARRS suppression[62 65 97 99ndash101]

52 VDR Silencing To studyVDR silencing theVDRknock-out (VDRminusminus) mouse model of deranged vitamin D-VDRsignaling and poor utilization of vitamin D in the CNS iswidely accepted Several phenotypes of the VDRminusminus mousehave been identified University of Tokyo (Japan) initiallygenerated VDR KO mice which show the signs of shortenedlifespan and premature aging Thus it is counted as animpressive model of VD and VDR deficiency as seen in


accelerated brain aging Cognitive and behavioral deficits andcalcium dysregulation in brain are also found to affect VDRKOmice [102ndash104]

VDR and NGF level are found to be suppressed asa result of amyloid beta toxicity [62] This reinforces theidea that vitamin D suppression is the reason behind thedecreased NGF levels in A120573 induced neurotoxicity It canbe presumed that A120573 induces VDR protein degradationtriggering some unknown mechanisms Inadequate vitaminD levels in AD patients along with VDR protein depletioncan precipitate a cascade of critical phenomenon All theseinformation point to the fact that even sufficient levels ofvitamin D are not enough for normal functioning as A120573can create hindrance by downregulating VDR [64] VDRsilencing can also upregulate LVSCC Ca channels In a studyby Gezen-Ak et al VDR siRNA-treated cortical neuronsshowed upregulated LVSCC-A1C mRNA levels after both 12and 24 hours of treatment compared to the control Proteinlevels followed the same trend [62]

53 VDR Polymorphism and AD The critical steps in thecontrol of gene expression by VDR include ligand bindingwith retinoidX receptor (RXR) heterodimerization and bind-ing of the heterodimer to VDR response elements (VDREs)Thus genetic polymorphisms of VDR gene can lead to defectsin important gene activations Polymorphisms can take placein the noncoding parts of the genes or introns whereby theyare not translated into the protein However polymorphismswithin the regulatory regions can affect the gene expressionPolymorphisms within the 51015840 promoter region of VDR geneaffectsmRNAexpression patterns and levelswhile thatwithinthe 31015840 untranslated region (UTR) affects mRNA stability[105] The existence of several single nucleotide polymor-phisms (SNPs)within theVDRgene has been described usingrestriction enzymes which include Tru9I TaqI BsmI EcoRVApaI and FokI [106ndash109] Using sequencing approachesCdx2 polymorphismwas found [110] Some of these commonVDR polymorphisms have been linked to AD Gezen-Ak etal reported the association of ApaI polymorphism and notTaqI polymorphism in late onset AD in the studied Turkishpopulation thereby indicating that polymorphism within theligand binding site of VDR gene increases the risk of ADprogression [100] However Lehmann et al and Lee et aldemonstrated the existence of possible links between ApaIandTaqIwith the risk ofAD [111 112]Wang et al reported theassociation between Cdx2 and lower VDR promoter activitythereby increasing susceptibility to AD [113] Thus VDRpolymorphismmay decrease the affinity of vitaminD toVDRand affect the expression of neurotrophins This can lead toneuronal aging and neurodegeneration in association withother genetic and environmental factors

6 Is Vitamin D Essential in AD Therapeutics

Despite several experimental in vivo or in vitro modelsof AD explaining its molecular pathogenesis which haveled to different types of drug treatment strategies and testsin animal and cell-based models and in clinical trials the

treatment of AD in general is terribly inadequate at presentThe disease progresses relentlessly with devastating failure ofmemory and cognition till the patient succumbs to the illnessusually by 5ndash9 years after the diagnosis A major focus ofthe drug treatment for AD is to improve cognitive abilitiessuch as memory and thinking and slow the progressionof these symptoms Four drugs are currently approved bythe US Food and Drug Administration (FDA) for treatingcognitive symptoms of AD Three of them (galantaminerivastigmine and donepezil) act as anticholinesterase agentswhile memantine acts by preventing excitatory neuronaldamage [114]

In general several strategies have been evolved to halt theprogression of the disease such as increasing the clearanceof amyloid beta peptide from the brain by active or passiveimmunization against the peptide or promoting enzymaticdegradation of the peptide diminishing the synthesis of A120573-42 by inhibition of 120573-secretases or 120574-secretases activation ofnonamyloidogenic processing of APP through modulationof 120573-secretase action preventing the aggregation and fibril-lization of A120573-42 inhibiting tau phosphorylation antibodiesagainst A120573 and reducing inflammation or oxidative stress orexcitotoxicity [114ndash116] Apparently either they are still in thetrial period or some trials have shown nonpromising results

The complexity of the mechanisms involved in AD hasprompted the researchers to develop compounds that couldsimultaneously interact with several potential targets (mul-titarget directed ligand design) [117] Variety of compoundswith dual or multiple target specificities are in developmentAs vitamin D interacts with different mechanisms thereforeit is a multitargeted therapeutic option for prevention andprotection from cognitive decline andADTheprotective roleof vitamin D in AD has been clearly established as discussedabove Now this is an important point when consideringrandomized controlled trials since it seems almost impossibleto get a trial approved to examine the effectiveness of vitaminD alone in AD andor ADRD patients after having removedstandard therapies A 7-year follow-up study by Annweileret al confirms that higher vitamin D dietary intake wasassociated with lower risk of developing AD among olderwomen [94] The AD-IDEA trial a randomized placebo-controlled trial was the first of such trials on the effectivenessof vitamin D in ADRD patients [118]

The trial of vitamin D alone or in combination with otheragentsanti-AD drugs have shown positive results in somerecent works Fiala and Mizwicki have shown that combineduse of vitamin D

3and DHA (Docosahexaenoic acid) is

an emerging novel strategy to enhance direct and immuneprotection of neurons against brain amyloidosis and otherbrain insults [119] As vitamin D targets various pathologicalprocesses of ADRDs it may increase the effectiveness ofstandard antidementia treatments or account at least partiallyfor the resistance to these treatments In support of thisfact a recent 6-month trial study by Annweiler et al hasshown that the combination of memantine and vitamin Dwas superior to either memantine or vitamin D alone inhalting the cognitive decline amongst participants with ADas evidenced by improved MMSE score [120]


In contrast one randomized control by Stein et al showedthat neither cognition nor disability changed significantlyafter high-dose vitamin D in mild to moderately severe ADcases [121] Another study also found no improvement ofcognition in an elderly nursing home residents after 4 weeksof oral vitamin D

2supplementation [122] These studies by

Stein etal or by Przybelski et al have shown no benefitsof high-dose vitamin D

2supplementation on cognition

[121 122] However there have been some methodologicallimitations that affected their conclusions For instance bothstudies monitored the role of vitamin D

2supplements which

are generally less efficient than vitamin D3for repletion

and duration of the follow-up that did not exceed 16 weekswhile the effects of vitamin D can be observed after alonger period [123] Additionally none of these studiesassessed executive functions or episodic memory as outcomemeasures although serum 25OH vitamin D concentrationsare associated with these domain-specific cognitive functions[124] The arguments against vitamin D supplementationare based on the small number of clinical trials Furtherwell-conducted randomized clinical trials (RCTs) to test theeffectiveness of vitamin D supplements against placebo inpatients with AD are essentially needed at this time

7 Conclusion and Future Directions

The pathophysiology of AD involves the accelerated agingof neurons leading to alteration in neuronal metabolismand stability A link between premature aging diet andnutrition is proposedwith nutrigenomic research uncoveringpossible mechanisms such as epigenetic modifications thatdemonstrate the interaction between genes and environmentdisturbances and imbalances occurring in a variety of mech-anisms It surprises that in spite of the wealth of knowledgethat exists regarding AD only a handful of options areavailable currently for its management The disease processis also complex in its own ways Symptomatic treatmentis the best part of the management currently Howeverexciting and incredible leaps have taken place in developingdisease modifying approaches The failed antiamyloid andantioxidant drug trials confirms that the understanding of theAD pathology still needs to be dissected out in every aspectDetailed exploration of the link between several metabolicand endocrine etiological factors gene-environment inter-actions and their influence on MCI and subsequent ADprogression are of prime focus now and treatment strategiesshould be looked up very carefully Inappropriate timing andthe long latency period of AD adds another dimension in itscomplexity wherein the principal mechanisms change withthe time course and progression of the disease Antioxidanttherapy may be helpful in the early stages of the diseasebut not when sufficient damage has already been doneOpposite is the case with memantine which is useful inmoderate to severe stages but not in early AD Multitargetedneuroprotective action of vitamin D makes it a lucrativecandidate for the prevention as well as treatment strategyin AD and ADRDs A recent task force on vitamin D andneurocognition has analysed all major studies and enabled

international experts to reach to the agreement that hypovita-minosis D and the inefficient utilization of vitaminD increasethe risk of cognitive declineADRDs in older adults andmay alter the clinical presentation of the disease particularlyas a sequel of accompanying morbidities [90] However atpresent hypovitaminosisD should not be used as a diagnosticor a prognostic biomarker of cognitive declineADRDs dueto lack of specificity and insufficient evidence The expertsrecommended measurement of serum 25(OH)D because ofthe high prevalence of hypovitaminosis D in this populationand supplementation if necessary However it is worthnoting that a very recent study has identified vitamin Dbinding protein to be a potential blood biomarker for thediagnosis of AD [125] However further verification withlarger epidemiological and molecular evidences is eagerlyawaited before targeting DBP as a possible therapeutic mod-ulation in AD

At this time further laboratory experiments prospectivestudies and large trials are essential to clarify themechanismsthrough which vitamin D benefits the brain A stronger focuson the role of vitamin D-related genetic variance (eg in thegenes encoding VDR 120572-hydroxylase or VDBP) in humansis also necessary in order to understand the prevalenceand therapeutic response In parallel conditional and brain-specific VDR mutations have to be identified to assess theirneurophenotypes Acute and chronic vitamin D treatment ordepletion should also be carried out in order to best interpretneurocognitive and behavioral abnormalities associated withvitamin D deprivation Further animal-based studies anddrug trials need to be conducted to determine the thresholdconcentration of vitamin D to prevent neurodegenerationso that the correct dose of supplementation could be deter-mined

Conflict of Interests

The authors declare that there is no conflict of interests

Acknowledgments

The authors thank the Department of Biotechnology Govtof India New Delhi for the financial support to our researchon Alzheimerrsquos disease Upasana Ganguly acknowledges theCouncil of Scientific and Industrial Research Govt of IndiaNew Delhi for their support and financial assistance Theauthors also thank ldquoThe West Bengal University of HealthSciencesrdquo for their help and encouragement

References

[1] C Mount and C Downton ldquoAlzheimer disease progress orprofitrdquo Nature Medicine vol 12 no 7 pp 780ndash784 2006

[2] C P Ferri M Prince C Brayne et al ldquoGlobal prevalence ofdementia a Delphi consensus studyrdquo The Lancet vol 366 no9503 pp 2112ndash2117 2005

[3] T J Montine W J Koroshetz and D Babcock ldquoRecommenda-tions of the Alzheimerrsquos disease-related dementias conferencerdquoNeurology vol 83 no 9 pp 851ndash860 2014


[4] H W Querfurth and F M LaFerla ldquoAlzheimerrsquos diseaserdquo TheNew England Journal of Medicine vol 362 no 4 pp 329ndash3442010

[5] D Pratico ldquoOxidative stress hypothesis in Alzheimerrsquos diseasea reappraisalrdquoTrends in Pharmacological Sciences vol 29 no 12pp 609ndash615 2008

[6] L H Kuller T J LittlejohnsW E Henley et al ldquoVitaminD andthe risk of dementia and Alzheimer diseaserdquoNeurology vol 83no 10 pp 920ndash928 2014

[7] N J Groves J J McGrath and T H J Burne ldquoVitamin D as aneurosteroid affecting the developing and adult brainrdquo AnnualReview of Nutrition vol 34 pp 117ndash141 2014

[8] C Annweiler M M Odasso S W Muir and O BeauchetldquoVitamin D and brain imaging in the elderly should we expectsome lesions specifically related to hypovitaminosis Drdquo TheOpen Neuroimaging Journal vol 6 pp 16ndash18 2012

[9] E D Michos and R F Gottesman ldquoVitamin D for the preven-tion of stroke incidence and disability promising but too earlyfor prime timerdquo European Journal of Neurology vol 20 no 1pp 3ndash4 2013

[10] L Jianlin T D Gould P Yuan et al ldquoPost mortem intervaleffects on the phosphorylation of signalling proteinsrdquoNeuropsy-chopharmacology vol 28 pp 1017ndash1025 2003

[11] J Gotz J R Streffer D David et al ldquoTransgenic animal modelsof Alzheimerrsquos disease and related disorders histopathologybehavior and therapyrdquo Molecular Psychiatry vol 9 no 7 pp664ndash683 2004

[12] J Wang D W Dickson J Q Trojanowski and V M-Y LeeldquoThe levels of soluble versus insoluble brain a120573 distinguishAlzheimerrsquos disease from normal and pathologic agingrdquo Exper-imental Neurology vol 158 no 2 pp 328ndash337 1999

[13] A C LeBlanc M Papadopoulos C Belair et al ldquoProcessingof amyloid precursor protein in human primary neuron andastrocyte culturesrdquo Journal of Neurochemistry vol 68 no 3 pp1183ndash1190 1997

[14] S H Choi Y H Kim M Hebisch et al ldquoA three-dimensionalhuman neural cell culture model of Alzheimerrsquos diseaserdquoNature vol 515 no 7526 pp 274ndash278 2014

[15] L Mucke and D J Selkoe ldquoNeurotoxicity of amyloid 120573-protein synaptic and network dysfunctionrdquoCold Spring HarborPerspectives in Medicine vol 2 no 7 Article ID a006338 2012

[16] M G Savelieff S Lee Y Liu and M H Lim ldquoUntanglingamyloid-120573 tau and metals in Alzheimerrsquos diseaserdquo ACS Chem-ical Biology vol 8 no 5 pp 856ndash865 2013

[17] G Perry A D Cash and M A Smith ldquoAlzheimer disease andoxidative stressrdquo Journal of Biomedicine and Biotechnology vol2 no 3 pp 120ndash123 2002

[18] R H Swerdlow and S M Khan ldquoA lsquomitochondrial cascadehypothesisrsquo for sporadic Alzheimerrsquos diseaserdquoMedical Hypothe-ses vol 63 no 1 pp 8ndash20 2004

[19] E Karran M Mercken and B D Strooper ldquoThe amyloidcascade hypothesis for Alzheimerrsquos disease an appraisal for thedevelopment of therapeuticsrdquo Nature Reviews Drug Discoveryvol 10 no 9 pp 698ndash712 2011

[20] W T Kimberly W Xia T Rahmati M S Wolfe and D JSelkoe ldquoThe transmembrane aspartates in presenilin 1 and 2are obligatory for 120574-secretase activity and amyloid 120573-proteingenerationrdquo Journal of Biological Chemistry vol 275 no 5 pp3173ndash3178 2000

[21] A E Roher J D Lowenson S Clarke et al ldquo120573-amyloid-(1-42) isa major component of cerebrovascular amyloid deposits impli-cations for the pathology of Alzheimer diseaserdquo Proceedings of

the National Academy of Sciences of the United States of Americavol 90 no 22 pp 10836ndash10840 1993

[22] M Ahmed J Davis D Aucoin et al ldquoStructural conversion ofneurotoxic amyloid-1205731ndash42 oligomers to fibrilsrdquo Nature Struc-tural and Molecular Biology vol 17 no 5 pp 561ndash567 2010

[23] C Reitz and R Mayeux ldquoAlzheimer disease epidemiologydiagnostic criteria risk factors and biomarkersrdquo BiochemicalPharmacology vol 88 no 4 pp 640ndash651 2014

[24] D K Lahiri and B Maloney ldquoThe lsquoLEARnrsquo (Latent Early-lifeAssociated Regulation) model integrates environmental riskfactors and the developmental basis of Alzheimerrsquos disease andproposes remedial stepsrdquo Experimental Gerontology vol 45 no4 pp 291ndash296 2010

[25] E V McCollum N Simmonds J E Becker and P G ShipleyldquoAn experimental demonstration of the existence of a vitaminwhich promotes calcium depositionrdquo The Journal of BiologicalChemistry vol 53 pp 293ndash298 1922

[26] H F DeLuca ldquoOverview of general physiologic features andfunctions of vitamin D 1ndash4rdquo The American Journal of ClinicalNutrition vol 80 no 6 pp 16895ndash16965 2004

[27] R Nair and A Maseeh ldquoVitamin D the sunshine vitaminrdquoJournal of Pharmacology and Pharmacotherapeutics vol 3 no2 pp 118ndash126 2012

[28] M F Holick J A MacLaughlin M B Clark et al ldquoPhoto-synthesis of previtamin D3 in human skin and the physiologicconsequencesrdquo Science vol 210 no 4466 pp 203ndash205 1980

[29] B Lehmann and M Meurer ldquoVitamin D metabolismrdquo Derma-tologic Therapy vol 23 no 1 pp 2ndash12 2010

[30] D E Prosser and G Jones ldquoEnzymes involved in the activationand inactivation of vitamin Drdquo Trends in Biochemical Sciencesvol 29 no 12 pp 664ndash673 2004

[31] M F Holick ldquoMedical progress vitamin D deficiencyrdquoTheNewEngland Journal of Medicine vol 357 no 3 pp 266ndash281 2007

[32] B Lehmann O Tiebel and M Meurer ldquoExpression of vitaminD325-hydroxylase (CYP27) mRNA after induction by vitamin

D3or UVB radiation in keratinocytes of human skin equiva-

lents a preliminary studyrdquo Archives of Dermatological Researchvol 291 no 9 pp 507ndash510 1999

[33] B Diesel M Seifert J Radermacher et al ldquoTowards a completepicture of splice variants of the gene for 25-hydroxyvitaminD31120572-hydroxylase in brain and skin cancerrdquo Journal of SteroidBiochemistry andMolecular Biology vol 89-90 no 1ndash5 pp 527ndash532 2004

[34] B Diesel J Radermacher M Bureik et al ldquoVitamin D3metabolism in human glioblastoma multiforme functionalityof CYP27B1 splice variants metabolism of calcidiol and effectof calcitriolrdquo Clinical Cancer Research vol 11 no 15 pp 5370ndash5380 2005

[35] M F Holick ldquoVitamin D and brain health the need forvitamin D supplementation and sensible sun exposurerdquo Journalof Internal Medicine vol 277 no 1 pp 90ndash93 2015

[36] G K Fu D Lin M Y H Zhang et al ldquoCloning of human 25-hydroxyvitamin D-1alpha-hydroxylase and mutations causingvitamin D-dependent rickets type 1rdquo Molecular Endocrinologyvol 11 no 13 pp 1961ndash1970 1997

[37] I Neveu P Naveilhan C Menaa D Wion P Brachet andM Garabedian ldquoSynthesis of 125-dihydroxyvitamin D3 by ratbrain macrophages in vitrordquo Journal of Neuroscience Researchvol 38 no 2 pp 214ndash220 1994

[38] P Naveilhan I Neveu C Baudet K Y Ohyama P Brachet andD Wion ldquoExpression of 25(OH) vitamin D3 24-hydroxylasegene in glial cellsrdquo NeuroReport vol 5 no 3 pp 255ndash257 1993


[39] D J Llewellyn K M Langa and I A Lang ldquoSerum 25-hydrox-yvitamin D concentration and cognitive impairmentrdquo Journalof Geriatric Psychiatry and Neurology vol 22 no 3 pp 188ndash1952009

[40] D Gezen-Ak S Yılmazer and E Dursun ldquoWhy vitamin Din Alzheimerrsquos disease the hypothesisrdquo Journal of AlzheimerrsquosDisease vol 40 no 2 pp 257ndash269 2014

[41] D W Eyles S Smith R Kinobe et al ldquoDistribution of thevitamin D receptor and 1 alpha-hydroxylase in human brainrdquoJournal of Chemical Neuroanatomy vol 29 pp 21ndash30 2005

[42] C AnnweilerMMontero-Odasso VHachinski S Seshadri RBartha and O Beauchet ldquoVitamin D concentration and lateralcerebral ventricle volume in older adultsrdquo Molecular Nutritionand Food Research vol 57 no 2 pp 267ndash276 2013

[43] M T Mizwicki D Menegaz J Zhang et al ldquoGenomic andnongenomic signaling induced by 112057225(OH)

2-vitamin D

3pro-

motes the recovery of amyloid-120573 phagocytosis by Alzheimerrsquosdiseasemacrophagesrdquo Journal of Alzheimerrsquos Disease vol 29 no1 pp 51ndash62 2012

[44] J C Fleet ldquoRapidmembrane-initiated actions of 125 dihydrox-yvitaminD what are they andwhat do theymeanrdquoThe Journalof Nutrition vol 134 no 12 pp 3215ndash3218 2004

[45] M K Sutherland M J Somerville L K K Yoong C BergeronM R Haussler and D R Crapper McLachlan ldquoReductionof vitamin D hormone receptor mRNA levels in Alzheimeras compared to Huntington hippocampus correlation withcalbindin-28k mRNA levelsrdquoMolecular Brain Research vol 13no 3 pp 239ndash250 1992

[46] T B Moore H P Koeffler J M Yamashiro and R K WadaldquoVitamin D3 analogs inhibit growth and induce differentiationin LA-N-5 human neuroblastoma cellsrdquo Clinical and Experi-mental Metastasis vol 14 no 3 pp 239ndash245 1996

[47] M C Langub J P Herman H H Malluche and N JKoszewski ldquoEvidence of functional vitamin D receptors in rathippocampusrdquo Neuroscience vol 104 no 1 pp 49ndash56 2001

[48] D Baas K Prufer M E Ittel et al ldquoRat oligodendro-cytes express the vitamin D

3receptor and respond to 125-

dihydroxyvitamin D3rdquo Glia vol 31 no 1 pp 59ndash68 2000

[49] T D Veenstra K Prufer C Koenigsberger S W Brimijoin JP Grande and R Kumar ldquo125-DihydroxyvitaminD3 receptorsin the central nervous system of the rat embryordquoBrain Researchvol 804 no 2 pp 193ndash205 1998

[50] E Bartoccini FMarini E Damaskopoulou et al ldquoNuclear lipidmicrodomains regulate nuclear vitamin D3 uptake and influ-ence embryonic hippocampal cell differentiationrdquo MolecularBiology of the Cell vol 22 no 17 pp 3022ndash3031 2011

[51] L Almeras D Eyles P Benech et al ldquoDevelopmental vitaminD deficiency alters brain protein expression in the adult ratimplications for neuropsychiatric disordersrdquo Proteomics vol 7no 5 pp 769ndash780 2007

[52] C Carlberg ldquoThe vitamin D3 receptor in the context of thenuclear receptor superfamily the central role of the retinoid Xreceptorrdquo Endocrine vol 4 no 2 pp 91ndash105 1996

[53] V C Yu C Delsert B Andersen et al ldquoRXR120573 a coregulatorthat enhances binding of retinoic acid thyroid hormone andvitamin D receptors to their cognate response elementsrdquo Cellvol 67 no 6 pp 1251ndash1266 1991

[54] S A Kliewer K Umesono D J Mangelsdorf and R M EvansldquoRetinoid X receptor interacts with nuclear receptors in retinoicacid thyroid hormone and vitamin D3 signallingrdquo Nature vol355 no 6359 pp 446ndash449 1992

[55] PNMacDonald T A BaudinoH TokumaruD RDowd andC Zhang ldquoVitamin D receptor and nuclear receptor coactiva-tors crucial interactions in vitamin D-mediated transcriptionrdquoSteroids vol 66 no 3-5 pp 171ndash176 2001

[56] J Brown J I Bianco J J McGrath and D W Eyles ldquo125-Dihydroxyvitamin D

3induces nerve growth factor promotes

neurite outgrowth and inhibits mitosis in embryonic rat hip-pocampal neuronsrdquo Neuroscience Letters vol 343 no 2 pp139ndash143 2003

[57] P Calissano C Matrone and G Amadoro ldquoNerve growthfactor as a paradigm of neurotrophins related to Alzheimerrsquosdiseaserdquo Developmental Neurobiology vol 70 no 5 pp 372ndash383 2010

[58] T D Veenstra M Fahnestock and R Kumar ldquoAn AP-1 sitein the nerve growth factor promoter is essential for 125-dihydroxyvitaminD

3-mediated nerve growth factor expression

in osteoblastsrdquo Biochemistry vol 37 no 17 pp 5988ndash5994 1998[59] S N Baksi and M J Hughes ldquoChronic vitamin D deficiency in

theweanling rat alters catecholaminemetabolism in the cortexrdquoBrain Research vol 242 no 2 pp 387ndash390 1982

[60] E Puchacz W E Stumpf E K Stachowiak and M KStachowiak ldquoVitamin D increases expression of the tyrosinehydroxylase gene in adrenal medullary cellsrdquo Molecular BrainResearch vol 36 no 1 pp 193ndash196 1996

[61] E Garcion N Wion-Barbot C N Montero-Menei F Bergerand D Wion ldquoNew clues about vitamin D functions in thenervous systemrdquoTrends in Endocrinology ampMetabolism vol 13no 3 pp 100ndash105 2002

[62] D Gezen-Ak E Dursun and S Yilmazer ldquoThe effects ofvitamin D receptor silencing on the expression of LVSCC-A1Cand LVSCC-A1D and the release of NGF in cortical neuronsrdquoPLoS ONE vol 6 no 3 Article ID e17553 2011

[63] L D Brewer V Thibault K-C Chen M C Langub P WLandfield and N M Porter ldquoVitamin D hormone confersneuroprotection in parallel with downregulation of L-typecalcium channel expression in hippocampal neuronsrdquo TheJournal of Neuroscience vol 21 no 1 pp 98ndash108 2001

[64] E Dursun D Gezen-Ak and S Yilmazer ldquoA novel perspectivefor Alzheimerrsquos disease vitamin D receptor suppression byamyloid-120573 and preventing the amyloid-120573 induced alterations byvitamin D in cortical neuronsrdquo Journal of Alzheimerrsquos Diseasevol 23 no 2 pp 207ndash219 2011

[65] D Gezen-Ak E Dursun and S Yilmazer ldquoVitamin D inquiryin hippocampal neurons consequences of vitamin D-VDRpathway disruption on calcium channel and the vitamin DrequirementrdquoNeurological Sciences vol 34 no 8 pp 1453ndash14582013

[66] E van Etten and C Mathieu ldquoImmunoregulation by 125-dihydroxyvitamin D3 basic conceptsrdquo The Journal of SteroidBiochemistry and Molecular Biology vol 97 no 1-2 pp 93ndash1012005

[67] D W Eyles F Feron X Cui et al ldquoDevelopmental vitaminD deficiency causes abnormal brain developmentrdquo Psychoneu-roendocrinology vol 34 no 1 pp S247ndashS257 2009

[68] J Moreno A V Krishnan D M Peehl and D FeldmanldquoMechanisms of vitamin D-mediated growth inhibition inprostate cancer cells inhibition of the prostaglandin pathwayrdquoAnticancer Research vol 26 no 4A pp 2525ndash2530 2006

[69] AVKrishnan andD Feldman ldquoMolecular pathwaysmediatingthe anti-inflammatory effects of calcitriol implications forprostate cancer chemoprevention and treatmentrdquo Endocrine-Related Cancer vol 17 no 1 pp R19ndashR38 2010


[70] A Masoumi B Goldenson S Ghirmai et al ldquo112057225-dihydrox-yvitamin D3 interacts with curcuminoids to stimulate amyloid-120573 clearance by macrophages of alzheimerrsquos disease patientsrdquoJournal of Alzheimerrsquos Disease vol 17 no 3 pp 703ndash717 2009

[71] S Ito S Ohtsuki Y Nezu Y Koitabashi S Murata andT Terasaki ldquo112057225-Dihydroxyvitamin D3 enhances cerebralclearance of human amyloid-120573 peptide(1ndash40) frommouse brainacross the blood-brain barrierrdquo Fluids and Barriers of the CNSvol 8 no 8 p 20 2011

[72] J YuM Gattoni-Celli H Zhu et al ldquoVitamin D3-enriched diet

correlates with a decrease of amyloid plaques in the brain ofA120573PP transgenic micerdquo Journal of Alzheimerrsquos Disease vol 25no 2 pp 295ndash307 2011

[73] G Carlberg ldquoThe concept of multiple vitamin D signalingpathwaysrdquo Journal of Investigative Dermatology SymposiumProceedings vol 1 no 1 pp 10ndash14 1996

[74] J Yanagisawa Y Yanagi Y Masuhiro et al ldquoConvergenceof transforming growth factor-120573 and vitamin D signalingpathways on SMAD transcriptional coactivatorsrdquo Science vol283 no 5406 pp 1317ndash1321 1999

[75] H Taniura M Ito N Sanada et al ldquoChronic vitamin D3 treat-ment protects against neurotoxicity by glutamate in associationwith upregulation of vitamin D receptor mRNA expression incultured rat cortical neuronsrdquo Journal of Neuroscience Researchvol 83 no 7 pp 1179ndash1189 2006

[76] M Ibi H Sawada M Nakanishi et al ldquoProtective effectsof 112057225-(OH)

2D3against the neurotoxicity of glutamate and

reactive oxygen species in mesencephalic culturerdquo Neurophar-macology vol 40 no 6 pp 761ndash771 2001

[77] V L Dawson and T M Dawson ldquoNitric oxide neurotoxicityrdquoJournal of Chemical Neuroanatomy vol 10 no 3-4 pp 179ndash1901996

[78] E Garcion S Nataf A Berod F Darcy and P Brachet ldquo125-DihydroxyvitaminD3 inhibits the expression of inducible nitricoxide synthase in rat central nervous system during experimen-tal allergic encephalomyelitisrdquo Molecular Brain Research vol45 no 2 pp 255ndash267 1997

[79] E Garcion L Sindji G Leblondel P Brachet and FDarcy ldquo125-dihydroxyvitamin D

3regulates the synthesis of 120574-

glutamyl transpeptidase and glutathione levels in rat primaryastrocytesrdquo Journal of Neurochemistry vol 73 no 2 pp 859ndash866 1999

[80] S Won I Sayeed B L Peterson et al ldquoVitamin D pre-vents hypoxiareoxygenation-induced blood-brain barrier dis-ruption via Vitamin D receptor-mediated NF-kB signalingpathwaysrdquo PLOS ONE vol 10 no 3 Article ID e0122821 2015

[81] T L Briones and H Darwish ldquoDecrease in age-related tauhyperphosphorylation and cognitive improvement followingvitamin D supplementation are associated with modulation ofbrain energy metabolism and redox staterdquo Neuroscience vol262 pp 143ndash155 2014

[82] D Eyles L Almeras P Benech et al ldquoDevelopmental vitaminD deficiency alters the expression of genes encoding mitochon-drial cytoskeletal and synaptic proteins in the adult rat brainrdquoJournal of Steroid BiochemistryampMolecular Biology vol 103 no3ndash5 pp 538ndash545 2007

[83] D W Eyles T H J Burne and J J McGrath ldquoVitamin Deffects on brain development adult brain function and the linksbetween low levels of vitamin D and neuropsychiatric diseaserdquoFrontiers in Neuroendocrinology vol 34 no 1 pp 47ndash64 2013

[84] M Moon H Song H J Hong et al ldquoVitamin D-binding pro-tein interacts with A120573 and suppresses A120573-mediated pathologyrdquoCell Death amp Differentiation vol 20 no 4 pp 630ndash638 2013

[85] T J Wang M J Pencina S L Booth et al ldquoVitamin Ddeficiency and risk of cardiovascular diseaserdquo Circulation vol117 no 4 pp 503ndash511 2008

[86] D J Llewellyn I A Lang K M Langa et al ldquoVitamin D andrisk of cognitive decline in elderly personsrdquo Archives of InternalMedicine vol 170 no 13 pp 1135ndash1141 2010

[87] C Annweiler and O Beauchet ldquoVitamin D-Mentia random-ized clinical trials should be the next steprdquo Neuroepidemiologyvol 37 no 3-4 pp 249ndash258 2011

[88] Y Slinin M L Paudel B C Taylor et al ldquo25-HydroxyvitaminD levels and cognitive performance and decline in elderly menrdquoNeurology vol 74 no 1 pp 33ndash41 2010

[89] T EtgenD SanderH Bickel K Sander andH Forstl ldquoVitaminD deficiency cognitive impairment and dementia a systematicreview and meta-analysisrdquo Dementia and Geriatric CognitiveDisorders vol 33 no 5 pp 297ndash305 2012

[90] C Balion L E Griffith L Strifler et al ldquoVitamin D cognitionand dementia a systematic review and meta-analysisrdquo Neurol-ogy vol 79 no 13 pp 1397ndash1405 2012

[91] J H Moon S Lim J W Han et al ldquoSerum 25-hydroxyvitaminD level and the risk of mild cognitive impairment and demen-tia the Korean Longitudinal Study on Health and Aging(KLoSHA)rdquo Clinical Endocrinology vol 83 no 1 pp 36ndash422015

[92] Y Slinin M L Paudel B C Taylor et al ldquo25-hydroxyvitaminD levels and cognitive performance and decline in elderly menrdquoNeurology vol 74 no 1 pp 33ndash41 2010

[93] C Annweiler M Montero-Odasso D J Llewellyn S Richard-Devantoy G Duque and O Beauchet ldquoMeta-analysis of mem-ory and executive dysfunctions in relation to vitaminDrdquo Journalof Alzheimerrsquos Disease vol 37 no 1 pp 147ndash171 2013

[94] C Annweiler Y Rolland A M Schott et al ldquoHigher vitaminD dietary intake is associated with lower risk of Alzheimerrsquosdisease a 7-year follow-uprdquo The Journals of Gerontology SeriesA Biological Sciences and Medical Sciences vol 67 no 11 pp1205ndash1211 2012

[95] C Anneweiler E Dursun F Feron et al ldquolsquoVitamin D andcognition in older adultsrsquo updated international recommenda-tionsrdquo Journal of Internal Medicine vol 277 no 1 pp 45ndash572015

[96] A Serretti P Olgiati and D De Ronchi ldquoGenetics ofAlzheimerrsquos disease A rapidly evolving fieldrdquo Journal ofAlzheimerrsquos Disease vol 12 no 1 pp 73ndash92 2007

[97] D Gezen-Ak E Dursun B Bilgic et al ldquoVitamin D receptorgene haplotype is associated with late-onset Alzheimerrsquos dis-easerdquo The Tohoku Journal of Experimental Medicine vol 228no 3 pp 189ndash196 2012

[98] E Dursun D Gezen-Ak and S Yilmazer ldquoBeta amyloidsuppresses the expression of the vitamin d receptor gene andinduces the expression of the vitamin D catabolic enzyme genein hippocampal neuronsrdquo Dementia and Geriatric CognitiveDisorders vol 36 no 1-2 pp 76ndash86 2013

[99] E Dursun D Gezen-Ak and S Yilmazer ldquoA new mechanismfor amyloid-120573 induction of iNOS vitamin D-VDR pathwaydisruptionrdquo Journal of Alzheimerrsquos Disease vol 36 no 3 pp459ndash474 2013


[100] D Gezen-Ak E Dursun T Ertan et al ldquoAssociation betweenvitamin D receptor gene polymorphism and Alzheimerrsquos dis-easerdquoTheTohoku Journal of ExperimentalMedicine vol 212 no3 pp 275ndash282 2007

[101] M A Beydoun E L Ding H A Beydoun T Tanaka L Fer-rucci and A B Zonderman ldquoVitamin D receptor and megalingene polymorphisms and their associations with longitudinalcognitive change in US adultsrdquoTheAmerican Journal of ClinicalNutrition vol 95 no 1 pp 163ndash178 2012

[102] T Keisala A Minasyan Y-R Lou et al ldquoPremature aging invitamin D receptor mutant micerdquo Journal of Steroid Biochem-istry and Molecular Biology vol 115 no 3ndash5 pp 91ndash97 2009

[103] A Minasyan T Keisala Y-R Lou A V Kalueff and PTuohimaa ldquoNeophobia sensory and cognitive functions andhedonic responses in vitamin D receptor mutant micerdquo Journalof Steroid Biochemistry and Molecular Biology vol 104 no 3ndash5pp 274ndash280 2007

[104] T H J Burne A N B Johnston J J McGrath and A MacKay-Sim ldquoSwimming behaviour and post-swimming activity inVitamin D receptor knockout micerdquo Brain Research Bulletinvol 69 no 1 pp 74ndash78 2006

[105] J M Valdivielso and E Fernandez ldquoVitamin D receptorpolymorphisms anddiseasesrdquoClinicaChimicaActa vol 371 no1-2 pp 1ndash12 2006

[106] W-Z Ye A F Reis andG Velho ldquoIdentification of a novel Tru9I polymorphism in the human vitaminD receptor generdquo Journalof Human Genetics vol 45 no 1 pp 56ndash57 2000

[107] N A Morrison J C Qi A Tokita et al ldquoPrediction of bone-density from vitamin D receptor allelesrdquo Nature vol 367 no6460 pp 284ndash287 1994

[108] N A Morrison R Yeoman P J Kelly and J A EismanldquoContribution of trans-acting factor alleles to normal physio-logical variability vitamin D receptor gene polymorphisms andcirculating osteocalcinrdquo Proceedings of the National Academy ofSciences of the United States of America vol 89 no 15 pp 6665ndash6669 1992

[109] J H Faraco N A Morrison A Baker J Shine and P MFrossard ldquoApaI dimorphism at the human vitamin-D receptorgene locusrdquo Nucleic Acids Research vol 17 no 5 p 2150 1989

[110] H Arai K-I Miyamoto M Yoshida et al ldquoThe polymorphismin the caudal-related homeodomain protein Cdx-2 bindingelement in the human vitaminD receptor generdquo Journal of Boneand Mineral Research vol 16 no 7 pp 1256ndash1264 2001

[111] D J Lehmann H Refsum D R Warden C Medway G KWilcock and A D Smith ldquoThe vitamin D receptor gene isassociated with Alzheimerrsquos diseaserdquo Neuroscience Letters vol504 no 2 pp 79ndash82 2011

[112] Y H Lee J-H Kim and G G Song ldquoVitamin D receptorpolymorphisms and susceptibility to Parkinsonrsquos disease andAlzheimerrsquos disease a meta-analysisrdquoNeurological Sciences vol35 no 12 pp 1947ndash1953 2014

[113] L Wang K Hara J M Van Baaren et al ldquoVitamin D receptorand Alzheimerrsquos disease a genetic and functional studyrdquoNeuro-biology of Aging vol 33 no 8 pp 1844e1ndash1844e9 2012

[114] R Anand K D Gill and A A Mahdi ldquoTherapeutics ofAlzheimerrsquos disease past present and futurerdquoNeuropharmacol-ogy vol 76 pp 27ndash50 2014

[115] Y Hong-Qi S Zhi-Kun and C Sheng-Di ldquoCurrent advances inthe treatment of Alzheimerrsquos disease focused on considerationstargeting A120573 and taurdquo Translational Neurodegeneration vol 1article 21 2012

[116] T Jiang J T Yu and L Tan ldquoNovel disease modifying therapiesfor Alzheimerrsquos diseaserdquo Journal of Alzheimerrsquos Disease vol 31no 3 Article ID 47592 2012

[117] M B H Youdim and J J Buccafusco ldquoCNS Targets formulti-functional drugs in the treatment of Alzheimerrsquos andParkinsonrsquos diseasesrdquo Journal of Neural Transmission vol 112no 4 pp 519ndash537 2005

[118] C Annweiler B Fantino E Parot-Schinkel SThiery J Gautierand O Beauchet ldquoAlzheimerrsquos diseasemdashinput of vitamin Dwith memantine assay (AD-IDEA trial) study protocol for arandomized controlled trialrdquo Trials vol 12 article 230 2011

[119] M Fiala and M T Mizwicki ldquoNeuroprotective and immuneeffects of active forms of vitamin D3 and docosahexaenoic acidin Alzheimer disease patientsrdquo Functional Foods in Health andDisease vol 1 no 12 pp 545ndash554 2011

[120] C Annweiler F R Herrmann B Fantino B Brugg and OBeauchet ldquoEffectiveness of the combination of memantine plusvitamin D on cognition in patients with Alzheimer disease apre-post pilot studyrdquo Cognitive amp Behavioral Neurology vol 25no 3 pp 121ndash127 2012

[121] M S Stein S C Scherer K S Ladd and L C Harrison ldquoA ran-domized controlled trial of high-dose vitamin D2 followed byintranasal insulin in Alzheimerrsquos diseaserdquo Journal of AlzheimerrsquosDisease vol 26 no 3 pp 477ndash484 2011

[122] R Przybelski S Agrawal D Krueger J A Engelke F Walbrunand N Binkley ldquoRapid correction of low vitamin D status innursing home residentsrdquo Osteoporosis International vol 19 no11 pp 1621ndash1628 2008

[123] K J Pepper S E Judd M S Nanes and V TangprichaldquoEvaluation of vitamin D repletion regimens to correct vitaminD status in adultsrdquo Endocrine Practice vol 15 no 2 pp 95ndash1032009

[124] M Schlogl and M F Holick ldquoVitamin D and neurocognitivefunctionrdquo Clinical Interventions in Aging vol 9 pp 559ndash5682014

[125] R J Bishnoi R F Palmer and D R Royall ldquoVitamin D bindingprotein as a serum biomarker of Alzheimerrsquos diseaserdquo Journal ofAlzheimerrsquos Disease vol 43 no 1 pp 37ndash45 2015

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


evidences studies in transgenic animal models and cell-based models (cell lines and primary cortical neurons) haveimproved our understanding of the pathogenesis of AD [10ndash14] These studies have implicated amyloid 120573 (A120573) accu-mulation hyperphosphorylated tau oxidative stress metaldysregulation mitochondrial dysfunction and inflamma-tory response as major interconnecting networks leadingto neuronal and synaptic degeneration [15ndash18] Alterationsin the amyloid metabolic cascade constitute an importanthypothesis in AD though none of the theories alone issufficient to decipher the biochemical and pathological com-plexities that result in disease progression [19] Corticalplaques in AD brain primarily contain A120573 protein which isproduced from its parent amyloid precursor protein (APP)through sequential hydrolysis by 120573 and 120574-secretases [20]The major species of A120573 are A120573-40 and A120573-42 peptidesand the latter is predominant in neuritic plaques and has ahigher propensity to aggregate and form the characteristictoxic amyloid fibrils in AD [21 22] In spite of evidences insupport of ldquoamyloid cascade hypothesisrdquo and ldquotauopathyrdquo itis still unclear how these events are triggered in the agingbrain and how they contribute to the complexity and the het-erogeneity of AD Moreover it has been established that theetiology of sporadic AD involves multiple gene-environmentinteractions as well as epigenetic mechanisms (as shownin Figure 1) working in the backdrop of aging brain [23]An interesting hypothesis in this regard is the Latent Early-life Associated Regulation (LEARn) model which proposesthat exposure to various environmental risk factors (heavymetals or nutritional deficiency) in the early developmentallife can bring about epigenetic modifications of AD relatedgenes (first hit) which remain latent for many years until asecond hit (aging elevated proinflammatory cytokines anddiet) results in sustained alterations in these genes promotingdisease progression [24]

3 Vitamin D Metabolism

Although vitamin D (calciferol) was discovered in the early20th century as a vitamin it is now recognized as a prohor-mone [25 26] Calciferols are a group of fat soluble secosterolsbroadly divided into twomajor forms ergocalciferol (vitaminD2) and cholecalciferol (vitamin D

3) [27] While vitamin

D2is largely found in food vitamin D

3is synthesized in

the human skin by a photochemical reaction (ultravioletB 297ndash315 nm) from 7-dehydrocholesterol [28] and is alsoconsumed in the diet Vitamin D in either D

2or D3

form is considered biologically inert until it undergoes twoenzymatic hydroxylation reactions First vitamin D bindscarrier proteins in the skin (particularly the vitamin Dbinding protein or DBPs) and is transported to the liver[29] where it is enzymatically hydroxylated by vitamin D-25-hydroxylase (CYP2R) on C-25 thereby generating 25(OH)Dor calcidiol A second hydroxylation reaction in the kidneyby 25(OH) D-1-OHase (CYP27B1) hydroxylates 25(OH)Dat C-1120572 position and converts it to the biologically activeform 125-dihydroxyvitamin D (125(OH)

2D) or calcitriol

[30] 125(OH)2D concentration in the blood is regulated by

a feedback mechanism and by the induction of parathyroidhormone Ca2+ and various cytokines Recent studies haveshown that in addition to renal cells various other cells (ker-atinocytes monocytes macrophages osteoblasts prostateand colon cells) are capable of carrying out the secondhydroxylation reaction [31ndash33] Circulating 25(OH) vitaminD crosses the blood-brain barrier and enters neuronal andglial cells to be converted to 125(OH)

2D [34 35] CYP27B1

has also been detected in developing human fetal brain[36] Recent data has shown that the central nervous systemcan locally perform bioactivation of vitamin D prohormoneand the presence of 1 120572-hydroxylase in human brain Inthis regard it is worth mentioning that microglial cells inculture produce 125(OH)

2D from its precursor [37] The

pattern of distribution of CYP27B1 in human and rat brainsis more or less consistent Previous studies have identified thepresence of another key enzyme CYP24A1 which is involvedin vitamin D catabolism in the human brain and also shownthat CYP24A1 mRNA has been induced by the treatment ofglial cells with 125 OH vitamin D [38] Thus 125(OH)

2D

is produced in various organs and cells functions in anautocrine pathway and leads to its own destruction byactivation of CYP24A1 which hydroxylates and oxidizes it toform the inactive calcitroic acid [30]

Recent evidences link serum vitamin D deficiency tocognitive impairment and dementia [39 40] Vitamin Dreceptors are widely expressed in the brain [41] Expressionof the active form of vitamin D regulates neurotrophinlevels and the survival of neural cells [42] In vitro studiesshow that vitamin D can stimulate the clearance of amyloidplaques by inducing phagocytosis by macrophages and alsoreduces the amyloid-induced cytotoxicity apoptosis andinflammatory responses in primary cortical neurons [43]Thus supplementation with vitamin D may ameliorate thecognitive deficits in the elderly people and control neuronalhealth and homeostasis

4 Vitamin D and Neuroprotection

The effects of vitamin D are exerted through its nuclearhormone receptor vitamin D receptor (VDR) or its mem-brane receptor membrane-associated rapid-response ster-oid-binding protein (125 MARRS) [44] Genomic andnongenomic actions of vitamin D are mediated by nuclearand membrane receptors respectively having identicalreceptor VDR in both locations Classical 125(OH)

2D

genomic signaling which is conducted through the VDRhas structural similarities with the nuclear steroid receptorfamily VDR gene is present on chromosome 12q1311 In 1992with the help of in situ hybridization studies it was proved forthe first time that VDR is expressed in the human brain [45]Expression of VDR mRNA in postmortem brains of patientswith Alzheimerrsquos or Huntingtonrsquos disease was identified usingradiolabeled cDNA probes Human neuroblastoma cell linewas also shown to express VDR [41 46] The presence ofVDR in the astrocytes is indicated by its presence in glialfibrillary acidic protein (GFAP) stained cells in primary rathippocampal cultures [41 47] Secondary oligodendrocyte


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