Table 2: The relationships of Alzheimer’s disease susceptibility genes with vitamin A. NF = none found.

GeneNameRelationships with vitamin A

Transport and entry
ALBAlbuminTogether with retinol binding protein forms the retinol transporter [39]
APOEApolipoprotein EExpression regulated by LXR/RXR dimers [40] Involved in retinyl palmitate transport [41]
TTRTransthyretin (prealbumin, amyloidosis type I)Carrier protein for the retinol binding protein [42]
APOA1Apolipoprotein A-IRORA target [43]: associates with transthyretin in plasma [44]
HSPG2Perlecan: (heparan sulfate proteoglycan 2)Binds to transthyretin [45]
A2MAlpha-2-macroglobulinSynthesis decreased in vitamin-A- deficient rats [46]
ABCA1ATP-binding cassette, subfamily A (ABC1), member 122R-hydroxycholesterol and 9-cis-retinoic acid induce ABCA1 expression and cholesterol efflux in brain cells and decrease Beta-amyloid secretion [47]. Involved in retinol and alpha- and gamma-tocopherol transport [48, 49]
CLUClusterin (APOJ) LRP2 ligandThe clusterin promoter contains a RARE sequence: Expression is suppressed by all-trans-retinoic acid [50]. Vitamin A deficiency increases clusterin expression in sertoli cells [51]
LRP2Low density lipoprotein-related protein 2 (clusterin receptor)Mediates the endocytosis of retinol via binding to retinol binding proteins and transthyretin [52, 53]
LRPAP1Low density lipoprotein receptor-related protein associated protein 1Regulates the uptake of retinol by LRP2 [54]

Metabolism
ALDH2Aldehyde dehydrogenase 2 family (mitochondrial)Exhibits low NAD(+)-dependent retinaldehyde activity [55]: regulated by RARB [56]
CYP46A1Cytochrome P450, family 46, subfamily A, polypeptide 1Synthesises 24-S hydroxycholesterol, a ligand for RARA and RARG [57]
GSTM1Glutathione S-transferase M1Weakly catalyses the enzymic isomerization of 13-cis-retinoic acid to all-trans-retinoic acid [58]
GSTP1Glutathione S-transferase piCatalyses the enzymic isomerization of 13-cis-retinoic acid to all-trans-retinoic acid [58]
LIPALipase A, lysosomal acid, cholesterol esterase (Wolman disease)Metabolises carotenoid mono- and diesters providing a source of free carotenoids in the gut [59]
LPLLipoprotein lipaseMetabolises retinyl esters [60]. RORA target [61]
LRATLecithin retinol acyltransferase (phosphatidylcholine—retinol O-acyltransferase)Lecithin retinol acyltransferase (phosphatidylcholine—retinol O-acyltransferase)
MEF2AMyocyte enhancer factor 2ARegulates beta-carotene 15,15′-monooxygenase 1 which cleaves beta-carotene to all-trans retinal and is the key enzyme in the intestinal metabolism of carotenes to vitamin A [62]

Receptors, coreceptors and receptor binding partners
CHD4Chromodomain helicase DNA binding protein 4Binds to RORG [63]
ESR1Estrogen receptor 1Dimerises with RAR and RXRA [52]
KLF5Kruppel-like factor 5 (intestinal)Binds to RARA [64]
NPAS2Neuronal PAS domain protein 2RAR alpha and RXR alpha bind to CLOCK and NPAS2 [65]. RORA target [66]
NR1H2Nuclear receptor subfamily 1, group H, member 2: liver X receptor betaLXRs form obligate heterodimers with retinoid X receptors RARA, RXRA, RXRB, RXRG (Entrez gene)
PARP1Poly (ADP-ribose) polymerase family, member 1Interacts with RARB [67]
PIN1Protein (peptidylprolyl cis/trans isomerase) NIMA-interacting 1RARalpha directly interacts with Pin1. Overexpression of Pin1 inhibits ligand-dependent activation of RARalpha [68]
POU2F1POU class 2 homeobox 1Binds to RXR [69]
PPARAPeroxisome proliferator-activated receptor alphaDimerises with RXRA and RXRG receptors [70]
PPARGPeroxisome proliferator-activated receptor gammaDimerises with RXRA receptors [71]
RXRARetinoid X receptor, alphaRetinoic acid receptor
THRAThyroid hormone receptor, alpha (erythroblastic leukemia viral (v-erb-a) oncogene homolog, avian)Dimerises with RXRA [72]
UBQLN1Ubiquilin 1Binds to retinoic acid receptor alpha [73]
VDRVitamin D (1,25-dihydroxyvitamin D3) receptorHeterodimerises with RXR and RARG [74]

APP and tau processing
APPAmyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)A gamma 57 gamma secretase cleavage product suppresses retinoid signalling [75]
BACE1Beta-site APP-cleaving enzyme 1Regulated by all-trans-retinoic acid [76]
NCSTNNicastrinBlocks the effects of retinoic acid on neurogenesis [77]
PSEN1Presenilin 1 (Alzheimer disease 3)Regulated by and regulates the effects of retinoic acid on neuronal differentiation [78, 79]
PSEN2Presenilin 2 (Alzheimer disease 4)Activated by all-trans-retinoic acid in osteoblasts [80]
CDK5Cyclin-dependent kinase 5Activated by retinoic acid [81]
GSK3BGlycogen synthase kinase 3 betaSH-SY5Y cells differentiate to neuron-like cells when treated with Retinoic acid/BDNF leading to increases in tau and tau phosphorylation, mediated primarily by GSK3B [82]: GSK3B inhibitors inhibit RARbeta-induced adipogenesis in mouse embryonic stem cells [83].
MAPTMicrotubule-associated protein tauPhosphorylation of tau at the 12E8 (Ser-262/Ser-356) epitope decreased in retinoic acid treated cells: increased at Ser-195/Ser-198/Ser-199/Ser-202) and (Ser-396/Ser-404) [84]

Viral and bacterial defence RIG-1, PKR, NOD and Toll receptor signalling
CARD8Caspase recruitment domain family, member 8NF
CD14CD14 moleculeExpression regulated by retinoids [85]: binds to H. Pylori lipopolysaccharide [86].
CD86CD86 moleculeExpression modulated by and the viral DNA minic polyriboinosinic:polyribocytidylic acid [87]
CST3Cystatin CNF antimicrobial peptide [88]
DEFB122Defensin, beta 122: Antimicrobial peptideNF
EIF2AK2Eukaryotic translation initiation factor 2-alpha kinase 2: (PKR activated by viral DNA)Upregulated by retinoic acid in HL-60 leukemia cells [89]
GBP2Guanylate binding protein 2, interferon inducibleNF
MEFVMediterranean feverNF
MPOMyeloperoxidaseAntimicrobial peptide [88], expression regulated by RXR/PPAR gamma heterodimer [90]
PIN1peptidylprolyl cis/trans isomerase, NIMA-interacting 1Binds to and negatively regulates IRF3 [91]
TFTransferrinAntimicrobial peptide [88]. Vitamin A deficiency is associated with modified iron homeostasis that can be reversed by retinoid supplementation, TF contains a peroxisome proliferator-activated receptor-retinoic acid X receptor heterodimer binding site [92]
TRAF2TNF receptor-associated factor 2Infection with RNA viruses activates the cytoplasmic retinoic acid-inducible gene-I (RIG-I) pathway which activates transcription factor IRF-3 which in turn induces many antiviral genes. It also induces apoptosis via TRAF2 [25]
TLR4Toll-like receptor 4Expression suppressed by retinoic acid [93]
PVRL2Poliovirus receptor-related 2 (herpesvirus entry mediator B)NF: herpes simplex receptor
ZBP1Z-DNA binding protein 1: DNA-dependent activator of interferon regulatory factorsNF

Cholesterol lipoprotein networks and lipid rafts
ABCA1Retinol transporter (see above)
ABCG1ATP-binding cassette, subfamily G (WHITE), member 1Expression regulated by 9-cis retinoic acid and 22-hydroxycholesterol [94]
APOA5Apolipoprotein A-VRegulated by RORA [95]. APOA5 polymorphisms modify lipoprotein bound retinyl palmitate concentrations [96]
APOC2Apolipoprotein C-IIExpression regulated by 9-cis-retinoic acid [97].
APOC3Apolipoprotein C-IIIRORA target [43]
APOC4Apolipoprotein C-IVExpression regulated by RXR ligands [98]
APODApolipoprotein DExpression regulated by RARA [99]
CETPCholesteryl ester transfer protein, plasmaExpression induced by 9-cis retinoic acid (RXR agonist) [100]
FDPSFarnesyl diphosphate synthase (farnesyl pyrophosphate synthetase, dimethylallyltranstransferase, geranyltranstransferase)Activated by the LXR/retinoid X receptor dimer [101]
LPALipoprotein, Lp(a)Isotretinoin reduces LPA serum levels [102]
LDLRLow-density lipoprotein receptor (familial hypercholesterolemia)NF
LRP1Low-density lipoprotein-related protein 1 (alpha-2-macroglobulin receptor)NF
LRP2See above (retinol receptor)
LRP6Low-density lipoprotein receptor-related protein 6Expression induced by retinoic acid [103]
LRP8Low-density lipoprotein receptor-related protein 8, apolipoprotein e receptorNF
NPC1Niemann-Pick disease, type C1NF
NPC2Niemann-Pick disease, type C2NF
OLR1Oxidized low-density lipoprotein (lectin-like) receptor 1NF
RFTN1Raftlin, lipid raft linker 1NF
SOAT1sterol O-acyltransferase 1: cholesterol acyltransferaseNF
SREBF1Sterol regulatory element binding transcription factor 1Liver X receptor/RXR target [104]
VLDLRVery-low-density lipoprotein receptorAll-trans retinoic acid increases expression in adenocarcinoma cells [105]

Chemokines and cytokines and inflammation
AGERAdvanced glycosylation end product-specific receptorExpression upregulated by retinol and vitamin A [106, 107]
ALOX5Arachidonate 5-lipoxygenaseRORA target [108]
CCL2Chemokine (C-C motif) ligand 2All-trans-retinoic acid suppresses bacterial lipopolysaccharide-induced expression and release in astrocytes [109]
CCL3Chemokine (C-C motif) ligand 3See CCL2 above
CCR2Chemokine (C-C motif) receptor 2Expression regulated by 9-cis-Retinoic acid [110]
IL10Interleukin 10All trans-retinoic acid increases IL10 production in monocytes and macrophages [111]
IL18Interleukin 18 (interferon-gamma-inducing factor)Differentiation of SH-SY5Y neuroblastoma cells by all-trans retinoic acid activates IL18 [112].
IL1AInterleukin 1, alphaRetinoic acid decreases expression in thymic epithelial cells [113]
IL1BInterleukin 1, betaIntraperitoneal retinoic acid reduces IL-1β, IL-6 and TNFα mRNA levels in the spinal cord after injury [114]. All-trans-retinoic acid increases IL1B expression in human aortic smooth muscle cells [115]
IL33Interleukin 33NF
IL6Interleukin 6 (interferon, beta 2)Retinoic acid increases expression in thymic epithelial cells [113].
IL8Interleukin 8Retinoid administration decreases polymorphonuclear neutrophilic leukocyte accumulation in mammary alveoli activated by lipopolysaccharide, and decreases IL-8 serum levels [116]
IL1RNinterleukin 1 receptor antagonistRetinoic acid enhances IL-1 beta and inhibited IL-1ra production in 4beta phorbol 12beta-myristate-13alpha acetate - and lipopolysaccharide-activated human alveolar macrophages [117].
PTGS2Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)Suppressed by RARB [118]
TGFB1Transforming growth factor, beta 1Repressed by RXRA.PPARG dimers [119]
TNFTumor necrosis factor (TNF superfamily, member 2)LPS from bacterial pathogens activates Retinoic inducible gene RIG-I which plays a key role in the expression of TNF-alpha in macrophages in response to LPS stimulation [120]
FASFas (TNF receptor superfamily, member 6)Retinoic acid increases the expression of FAS in adipocytes: all-trans retinoid acid reduces FAS expression in HELA cells

Complement and immune system
C4AComplement component 4A (Rodgers blood group)Complement C4 levels correlate with those of retinol in plasma [121]
C4BComplement component 4B (Chido blood group)See above
CFHComplement factor HExpression controlled by RAR beta [122]
CLUClusterinSee above
CR1Complement component (3b/4b) receptor 1 (Knops blood group)NF
CRPC-reactive protein, pentraxin relatedSerum CRP levels negatively correlate with vitamin A levels [123]
CD33CD33 moleculeNF
CD36CD36 molecule (thrombospondin receptor)RORA target [61]
HLA-AMajor histocompatibility complex, class I, AUpregulated by differentiation of teratoma cells into neuronal cells by retinoic acid [124]
HLA-A2Major histocompatibility complex, class I, A2Upregulated by interferon alpha-2b and retinoic acid combined treatment in cervical cancer cells [125]
MICAMHC class I polypeptide-related sequence AExpression upregulated by retinoic acid in hepatic carcinoma cells [126]

Oestrogen and androgen related
ARAndrogen receptor (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease)
ESR1See above
ESR2Estrogen receptor 2 (ER beta)9-cis retinoic acid stimulates expression in breast cancer cells [127]
CYP19A1Cytochrome P450, family 19, subfamily A, polypeptide 1: aromatase: estrogen synthaseActivated by RORA [128]
HSD11B1Hydroxysteroid (11-beta) dehydrogenase 1NF

Growth factor networks
BDNFBrain-derived neurotrophic factorExpression regulated by RARalpha/beta and vitamin A [129, 130], but all-trans retinoic acid reduces BDNF and TrkB gene expression in SH-SY5Y cells [131]
CSKC-src tyrosine kinaseCSK negatively regulates RAR functions in relation to neurite differentiation [132]
FGF1Fibroblast growth factor 1 (acidic)Protects fibroblasts from apoptosis induced by retinoid CD437 [133]
GAB2GRB2-associated binding protein 2Gab2 silencing results in hypersensitivity to retinoic acid -induced apoptosis in neuronal cells [134]
IGF1Insulin-like growth factor 1 (somatomedin C)Pulmonary expression reduced in RORalpha knockout mice [135]
NTRK1Neurotrophic tyrosine kinase, receptor, type 1Retinoic acid restores adult hippocampal neurogenesis and reverses spatial memory deficit in vitamin-A-deprived rats, partly by upregulating NTRK1 (TrkA) [136]
NTRK2Neurotrophic tyrosine kinase, receptor, type 2All-trans retinoic acid reduces BDNF and TrkB gene expression in SH-SY5Y cells [131]
VEGFAvascular endothelial growth factor AExpression regulated by retinoid acid [137]
Other signalling
DKK1Dickkopf homolog 1 (Xenopus laevis)Expression regulated by retinoic acid in stem cells [103]
DPYSL2Dihydropyrimidinase-like 2Upregulated in cortex and hippocampus by Vitamin A depletion [138]

Homocysteine and methionine metabolism
BLMHBleomycin hydrolaseHydrolyses homocysteine thiolactone [139]
CBSCystathionine-beta-synthaseConverts homocysteine to cystathionine suppressed by all-trans-retinoic acid [140]
MSRAmethionine sulfoxide reductase ARegulated by retinoic acid via two promoters including RARA [141]
MTHFD1LMethylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-likeNF
MTHFR5,10-methylenetetrahydrofolate reductase (NADPH)Methylenetetrahydrofolate reductase activity is suppressed in retinol-fed rats [142]
MTR5-methyltetrahydrofolate-homocysteine methyltransferaseIn rats, a retinol-rich diet enhances the folate-dependent oxidation to CO2 of formate and histidine. The activity of hepatic methylenetetrahydrofolate reductase, which regulates liver folate metabolism, is suppressed, leading to decreased 5-methyltetrahydrofolate synthesis [142]
MTRR5-methyltetrahydrofolate-homocysteine methyltransferase reductaseNF
PON1Paraoxonase 1 Hydrolyses homocysteine thiolactone [143]: vitamin A deficiency reduced serum PON1 activity in rats [144].

Oxidative stress, Iron and mitochondria
COX1Mitochondrially encoded cytochrome c oxidase I9-cis retinoic acid treatment increases mitochondrial DNA transcription, including ND1, ND6, and COX1 [145]
COX2Mitochondrially encoded cytochrome c oxidase IIExpression increased by all-trans retinoic acid [146]
GAPDHGlyceraldehyde-3-phosphate dehydrogenaseRetinoic acid target [147]
GSTM3Glutathione S-transferase M3 (brain)Contains a retinoid X receptor-binding site [148]
HBG2Hemoglobin, gamma GVitamin A increases haemoglobin concentrations in children [149]
HFEhemochromatosisNeuroblastoma cells carrying the C282Y HFE variant do not differentiate when exposed to retinoic acid [150]
HMOX1Heme oxygenase (decycling) 1The increase in the expression of heme oxygenase-1 and the growth arrest and DNA damage-inducible transcription factor 153 caused by reactive oxygen species is blocked by aRARalpha-specific antagonist AGN194301 in retinal epithelial cells [151]
ND1NADH dehydrogenase subunit 19-cis retinoic acid treatment increases mitochondrial DNA transcription, including ND1, ND6, and COX1 [145]
ND4NADH dehydrogenase subunit 4Upregulated by all-trans retinoic acid in neutrophils [152]
ND6NADH dehydrogenase subunit 69-cis retinoic acid treatment increases mitochondrial DNA transcription, including ND1, ND6, and COX1 [145]
NFE2L2Nuclear factor (erythroid-derived 2)-like 2Inhibited by retinoic acid via RARalpha resulting in lack of expression of Nrf2 target genes [153] in mammary cells, but retinoic acid and 12-O-tetradecanoylphorbol acetate are also able to induce Nrf2 and its target gene NAD(P)H quinone oxidoreductase 1 in the SH-SY5Y neuroblastoma cell line [154].
NOS1Nitric oxide synthase 1 (neuronal)Expression regulated by retinoic acid [84]
NOS2Nitric oxide synthase 2, inducibleDitto
NOS3Nitric oxide synthase 3 (endothelial cell)Ditto
NQO1NAD(P)H dehydrogenase, quinone 1Retinoic acid (RA) and 12-O-tetradecanoylphorbol acetats are able to induce Nrf2 and its target gene NAD(P)H quinone oxidoreductase 1 in the SH-SY5Y neuroblastomacell line [154]
SOD2Superoxide dismutase 2, mitochondrialAll-trans-retinoic acid induces manganese superoxide dismutase in a human neuroblastoma cell line [155]
PCK1Phosphoenolpyruvate carboxykinase 1 (soluble)Three RXR-binding elements (retinoic acid response element (RARE)1/PCK1, RARE2, and RARE3/PCK2) are located in the promoter of Pck1 [156]
PON2Paraoxonase 2NF
PON3Paraoxonase 3NF
TFAMTranscription factor A, mitochondrialLevels are increased by vitamin A [157]

Heat shock
DNAJC28DnaJ (Hsp40) homolog, subfamily C, member 28NF
HSPA1BHeat shock 70 kDa protein 1BNF
HSPA5Heat shock 70 kDa protein 5 (glucose-regulated protein, 78 kDa)Endoplasmic reticulum stress is increased in hepatocarcinoma cells by all-trans retinoic acid, characterised by increased expression of HSPA5 (grp78), GADD153, and XBP1[158]

Monoamine networks   
ADRB1Adrenergic, beta-1-, receptorRARA target [159]
ADRB2Adrenergic, beta-2-, receptor, surfaceExpression regulated by all-trans retinoic acid [160]
COMTCatechol-O-methyltransferaseExpression stimulated by all-trans retinoic acid [161]
PNMTPhenylethanolamine N-methyltransferaseRetinoic acid differentiates embryonic carcinoma cells into neuronal cells, 70% of which stain for tyrosine hydroxylase, dopamine beta-hydroxylase, and phenylethanolamine N-methyltransferase [162].

Cholinergic
CHATCholine acetyltransferaseExpression controlled by retinoic acid [163]
CHRNA3Cholinergic receptor, nicotinic, alpha 3Expression increased by retinoid acid [164]
CHRNA4Cholinergic receptor, nicotinic, alpha 4Expression decreased by retinoic acid [164]
CHRNB2Cholinergic receptor, nicotinic, beta 2 (neuronal)Expression increased by retinoid acid [164]

Neuropeptide
GRNGranulinAll-trans retinoic acid increases expression in myeloid cells [165]

Adhesion and proteoglycans
ACANAggrecanExpression modulated by 13-cis retinoic acid in fibroblasts [166]
ICAM1Intercellular adhesion molecule 1 (CD54), human rhinovirus receptorAll-trans retinoic acid downregulates ICAM1 expression in bone marrow stromal cells [167]

Structural, dynamins, and kinesins
COL11A1Collagen, type XI, alpha 1Expression controlled by all-trans-retinoic acid [168]
DSC1Desmocollin 1Retinoic acid decreases expression in oral keratinocytes [169]
LMNALamin A/C (nuclear)Promoter contains a retinoic acid-responsive element (L-RARE) [170]

Ubiquitin
UBDUbiquitin DAll-trans retinoic acid activated the ubiquitin/proteasome pathway in human acute myeloid leukemia cell lines [171]
UBE2IUbiquitin-conjugating enzyme E2I (UBC9 homolog, yeast)See above

DNA repair
XRCC1X-ray repair complementing defective repair in Chinese hamster cells 1N-[4-hydroxyphenyl] retinamide induces apoptosis in bladder cancer cell line and downregulates XRCC1 [172]

Cell cycle and tumour
CDC2Cell division cycle 2, G1 to S, and G2 to MActivated by retinoic acid [173]

Miscellaneous metabolism
ACAD8Acyl-coenzyme A dehydrogenase family, member 8Catalyzes the dehydrogenation of acyl-CoA derivatives in the metabolism of fatty acids or branch chained amino acids. The encoded protein is a mitochondrial enzyme that functions in catabolism of the branched-chain amino acid valine.
ALDH18A1Aldehyde dehydrogenase 18 family, member A1NF the encoded protein catalyzes the reduction of glutamate to delta1-pyrroline-5-carboxylate, a critical step in the de novo biosynthesis of proline, ornithine and arginine.
ARSAArylsulfatase A: hydrolyzes cerebroside sulfate to cerebroside and sulphateIncreased urinary excretion of both arylsulfatases A and B is increased in cases of severe vitamin A deficiency coupled with malnutrition [174]
ELAVL4ELAV (embryonic lethal, abnormal vision, drosophila)-like 4 (Hu antigen D)Inhibition reduces retinoic acid-induced neuronal differentiation of mouse embryonal carcinoma P19 cells [175]
SGPL1Sphingosine-1-phosphate lyase 1Treatment of F9 embryonal carcinoma cells with retinoic acid induces differentiation to primitive endoderm (PrE). This effect is attenuated by SGPL1 knockout [176].

Miscellaneous
CELF2CUGBP, Elav-like family member 2Splicing regulated by retinoic acid [177]
CUBNCubilin (intrinsic factor-cobalamin receptor)Expression regulated by all-trans-retinoic acid [178]
F13A1Coagulation factor XIII, A1 polypeptideVitamin A reduces factor XIII levels in rats fed an atherogenic diet [179].
HHEXHematopoietically expressed homeoboxAll-trans retinoic acid enhances expression in normal and tumorous mammary tissue [180]
NEDD9Neural precursor cell expressed, developmentally downregulated 9Downstream target of all-trans retinoic acid and its receptors in the human SH-SY5Y neuroblastoma cell line [181]
RELNReelinRetinoic acid-induced differentiation of NT2 cells to hNT neurons increases reelin expression [182].
RNR1RNA, ribosomal 1NF
RPS3ARibosomal protein S3ADownregulated by retinoid-induced differentiation of HL-60 cells [183]
RUNX1Runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene)RUNX1 knockdown inhibits retinoid-induced differentiation of HL-60 myeloid leukaemia cells [184].
SEPT3Septin 3Expressed in SH-SY5Y, after retinoic acid-induced differentiation [185]  
SNCASynuclein, alpha (non-A4 component of amyloid precursor)Vitamin A, beta-carotene and coenzyme Q10 inhibit the formation of synuclein fibrils [186]
SYN3Synapsin IIISynapsins including SYN3 are upregulated by retinoic acid-induced differentiation of NTera-2cl.D1 cells [187]
TARDBPTAR DNA binding proteinNF
VCPValosin-containing proteinRetinoic acid receptor responder (RARRES1) regulates VCP expression in human prostatic epithelial cells [188]