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Epigenetics of Brain Disorders: The Paradigm of Alzheimer's Disease | OMICS International
ISSN: 2161-0460
Journal of Alzheimers Disease & Parkinsonism

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Epigenetics of Brain Disorders: The Paradigm of Alzheimer's Disease

Ramón Cacabelos1,2*

1Chairman of Genomic Medicine, Camilo Jose Cela University, Madrid, Spain

2EuroEspes Biomedical Research Center, Institute of Medical Science and Genomic Medicine, Corunna, Spain

Corresponding Author:
Ramon Cacabelos
EuroEspes Biomedical Research Center
Institute of Medical Science and Genomic Medicine
15165-Bergondo,Corunna, Spain
Tel: +34-981-780505;
E-mail: [email protected]

Received date: October 01, 2015; Accepted date: April 04, 2016; Published date: April 11, 2016

Citation: Cacabelos R (2016) Epigenetics of Brain Disorders: The Paradigm of Alzheimer’s Disease. J Alzheimers Dis Parkinsonism 6:229. doi: 10.4172/2161-0460.1000229

Copyright: © 2016 Cacabelos R. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Over 80% of brain disorders are associated with multiple genomic defects in conjunction with environmental factors and epigenetic phenomena. Classical epigenetic mechanisms, including DNA methylation, histone modifications, and microRNAs (miRNAs) regulation, are among the major regulatory elements that control metabolic pathways at the molecular level, with epigenetic modifications controlling gene expression transcriptionally and miRNAs suppressing gene expression post-transcriptionally. Epigenetic modifications are related to disease development, environmental exposure, drug treatment and aging. Epigenetic changes are reversible and can be potentially targeted by pharmacological intervention. Both hypermethylation and hypomethylation of DNA, chomatin changes and miRNA dysregulation are common in age-related disorders and in many neuropsychiatric, neurodevelopmental and neurodegenerative disorders. Major epigenetic mechanisms may contribute to Alzheimer’s disease (AD) pathology. Several pathogenic genes and many other AD-related susceptibility genes contain methylated CpG sites. AD brains exhibit a genome-wide decrease in DNA methylation. Pathogenic histone modifications are present in AD. Alterations in epigentically regulated miRNAs may contribute to the abnormal expression of pathogenic genes in AD. Epigenetic drugs can reverse epigenetic changes in gene expression and might open future avenues in AD therapeutics. Individual differences in drug response are associated with genetic and epigenetic variability and disease determinants. Pharmacoepigenomics deals with the influence that epigenetic alterations may exert on genes involved in the pharmacogenomic network (pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes) responsible for the pharmacokinetics and pharmacodynamics of drugs (efficacy and safety), as well as the effects that drugs may have on the epigenetic machinery.

Keywords

Alzheimer’s disease; Brain disorders; Epigenetics; Epigenetic drugs; Pharmacogenomics; Pharmaco epigenomics

Introduction

Over 80% of central nervous system (CNS) disorders are polygenic/ complex disorders in which multiple defects distributed across the human genome are involved. The interaction of these pathogenic variants with diverse environmental factors and epigenetic phenomena result in the phenotypic expression of the disease [1-3]. Epigenetics involves heritable alterations of gene expression, chromatin organization, and microRNA (miRNA) regulation without changes in DNA sequence. Classical epigenetic mechanisms, including DNA methylation and histone modifications, and regulation by microRNAs (miRNAs), are among the major regulatory elements that control metabolic pathways at the molecular level, with epigenetic modifications regulating gene expression transcriptionally and miRNAs suppressing gene expression post-transcriptionally [4]. Epigenetic mechanisms are crucial to stabilize cell type-specific gene-expression programs [5]. Vertebrate genomes undergo epigenetic reprogramming during development and disease. Stable transmission of DNA methylation, transcriptomes and phenotypes from parent to clonal offspring are demonstrated in various asexual species, and clonal genotypes from natural populations show habitat-specific DNA methylation [6]. Methylation varies spatially across the genome with a majority of the methylated sitess mapping to intragenic regions [7]. Not only nuclear DNA (nDNA), but also mitochondrial DNA (mtDNA) may be subjected to epigenetic modifications related to disease development, environmental exposure, drug treatment and aging. mtDNA methylation is attracting increasing attention as a potential biomarker for the detection and diagnosis of diseases and the understanding of cellular behavior [8].

About 70% of CpG dinucleotides within the human genome are methylated. The transfer of methyl groups in CpGs is catalyzed by DNA methyl transferases (DNMT1, DNMT3A, DNMT3B).The enzymes involved in DNA de methylation include TET (ten-eleven translocation family), AID/APOBEC family, and the VER glycosylase family [9]. Histone acetylation is achieved by histone acetyltransferase (HAT); and histone deacetylation is produced by histone deacetylases (HDACs) (class I: HDAC1, 2, 3, and 8; class IIa: HDAC4, 5,7, and 9; class IIb: HDAC6 and 10; class III: SIRT1, 2, 6, 7; class IV: HDAC11) [9].

Long non-coding (lnc) RNAs are non-protein-coding RNAs, distinct from housekeeping RNAs (tRNAs, rRNAs, and snRNAs) and independent from small RNAs with specific molecular processing machinery. Over 95% of the eukaryotic genome is transcribed into non-coding RNAs and less than 5% is translated. LncRNA-mediated epigenetic regulation depends on lcnRNA interactions with proteins or genomic DNA via RNA secondary structures [10].

Epigenomic modifications are involved in a great variety of physiological and pathological conditions; of major importance are those related with major problems of health such as cardiovascular disorders, obesity, cancer, inflammatory processes, and brain disorders [11,12]. A good paradigm on the influence of epigenetic factors on human pathology is the oncogenic process in some types of cancer. For instance, myelodysplastic syndromes (MDS) are clonal diseases of the elderly characterized by chronic cytopenias, dysplasia, and a variable risk of progression to acute myeloid leukemia (AML). Aberrant methylation of tumor suppressor gene promoters has been established, suggesting that these alterations are drivers of MDS pathogenesis [13]. Epigenetic modifications are reversible and can be targeted by pharmacological intervention [14-17].

Brain disorders

Both hypermethylation and hypomethylation of DNA, chomatin changes and miRNA dysregulation are common in age-related disorders and in multiple modalities of brain disorders [9,15-17]. Altered DNA methylation patterns may account for phenotypic changes associated with human aging. Brain region-specific expression of genes can be epigenetically regulated by DNA methylation [18] and brain aging might be influenced by epigenetic changes in the neuronal microenvironment [19,20].

There are neurodevelopmental disorders in which epigenetic dysregulation plays an important role (autism spectrum disorders, Rett syndrome, fragile X syndrome, Prader-Willi syndrome, Angelman syndrome, and Kabuki syndrome [21-23]. Fragile X syndrome (FXS) is the most common monogenic form of developmental cognitive impairment with “dynamic” mutations of a CGG repeat in the 5’UTR of the FMR1 gene which is inactivated by DNA methylation and histone deacetylation [24]. Rett syndrome (RTT) is an X-linked neurodevelopmental disease caused by MECP2 mutations. The MeCP2 protein acts as a transcription repressor by binding to methylated CpG dinucleotides, and also as a transcription activator. MeCP2 is expressed in neurons and in glial cells. Reintroduction of MeCP2 into behaviorally-affected Mecp2-null mice after birth rescues neurological symptoms, indicating that epigenetic failures in RTT are reversible [25].

A growing number of congenital disorders have been linked to genomic imprinting which is caused by perturbed gene expression at one principal imprinted domain. Some imprinting disorders, including the Prader-Willi and Angelman syndromes, are caused almost exclusively by genetic mutations. In several others, including the Beckwith-Wiedemann and Silver-Russell growth syndromes, and transient neonatal diabetes mellitus, imprinted expression is perturbed mostly by epigenetic alterations at ‘imprinting control regions’ and at other specific regulatory sequences. In a minority of these patients, DNA methylation is altered at multiple imprinted loci, suggesting that common trans-acting factors are affected [26]. Maternal UPD for chromosome 7 (matUPD7) results in Silver-Russell syndrome (SRS) with typical features and growth retardation, but no gene has been conclusively implicated in SRS. Genome-scale analysis of eight matUPD7 patients, a segmental matUPD7q31-qter, a rare patUPD7 case and ten controls on the Infinium HumanMethylation450K Bead Chip with 30,017 CpG methylation probes for chromosome 7 showed highly significant clustering of DMRs only on chromosome 7, including the known imprinted loci GRB10, SGCE/PEG10, and PEG/MEST. Ten novel DMRs on chromosome 7, two DMRs for the predicted imprinted genes HOXA4 and GLI3 and one for the disputed imprinted gene PON1, and differential expression for three genes with novel DMRs, HOXA4, GLI3, and SVOP, were also demonstrated. Allele-specific expression analysis confirmed maternal only expression of SVOPL and imprinting of HOXA4 was supported by monoallelic expression. These results reported by Hannula-Jouppi et al. [27] represent the first comprehensive map of parent-of-origin specific DMRs on human chromosome 7, suggesting many new imprinted sites.

A body of novel arguments postulates the involvement of epigenetic mechanisms in the pathogenesis of autism. Mbadiwe and Millis [28] reviewed mechanisms for altering DNA-histone interactions of cell chromatin to upregulate or downregulate gene expression that could serve as epigenetic targets for therapeutic interventions. Quality of maternal care experienced during infancy is a key factor that can confer vulnerability or resilience to psychiatric disorders later in life. Experiences within an adverse caregiving environment produce aberrant DNA methylation patterns at various gene loci in the medial prefrontal cortex of developing and adult experimental animals [29].

Altered DNA methylation at the aryl hydrocarbon receptor repressor (AHRR) correlates with self-reported smoking. Smoking was associated with DNA demethylation at two distinct loci within AHRR (cg05575921 and cg21161138), and methylation status at the AHRR residue interrogated by cg05575921 was highly correlated with serum cotinine levels [30].

Epigenetic changes are also determinant in several neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease or Huntington’s disease [9,15,16,31,32].

Alzheimer’s disease

Alzheimer’s disease (AD) is a major problem of health in developed countries. AD affects approximately 5.4 million individuals in the United States and is estimated to affect up to 16 million by 2050 [33]. In Western countries, AD is the most prevalent form of dementia (45-60%), followed by vascular dementia (VD) (30-40%), and mixed dementia (10-20%), which in people older than 85 years of age may account for over 80% of the cases. The different forms of dementia pose several challenges to our society and the scientific community: (i) they represent an epidemiological problem, and a socio-economic, psychological and family burden; (ii) most of them have an obscure/ complex pathogenesis; (iii) their diagnosis is not easy and lacks specific biomarkers; and (iv) their treatment is difficult and inefficient [2,3,31,34,35]. In terms of economic burden, approximately 10-20% of direct costs are associated with pharmacological treatment, with a gradual increase in parallel with the severity of the disease.

Pathogenesis

Our understanding of the pathophysiology of dementia, parkinsonism and other CNS disorders, has advanced dramatically during the last 30 years, especially in terms of their molecular pathogenesis and genetics. Improvement in terms of clinical outcome, however, has fallen short of expectations, in spite of efforts to identify optimal treatment regimes with one or more drugs. Potential reasons to explain this historical setback might be that: (i) the molecular pathology of dementia is still poorly understood; (ii) drug targets are inappropriate, not fitting into the real etiology of the disease; (iii) most treatments are symptomatic, but not anti-pathogenic; (iv) the genetic and epigenetic component of dementia is poorly defined; and (v) the understanding of genome-drug interactions is very limited [2,3,34-36].

In general terms, AD is a polygenic/complex disorder in which hundreds of defective genes distributed across the human genome are involved in close interaction with environmental factors, cerebrovascular dysfunction, and epigenetic changes. A growing body of information suggests that diverse epigenetic phenomena may be involved in the pathogenesis of AD; however, this field is still in a very primitive stage [9,15,16,34-38].

AD is a multifactorial, polygenic/complex disorder characterized by (i) a clinical picture with progressive memory decline, behavioral changes, and functional deterioration, (ii) neuropathological hallmarks represented by deposits of extracellular Aβ aggregates in senile plaques, cytoskeletal abnormalities with intracellular neurofibrillary tangles (NFTs) resulting from the hyperphosphorylation of the tau protein, neuronal loss, and dendritic desarborization, and (iii) a myriad of neurochemical changes and mechanistic dysfunctions which altogether conform the pathogenic phenotype of the disease. The genomic, epigenomic, proteomic, and metabolomic changes underlying these phenotypic features are candidate targets for therapeutic intervention [3].

Genomics

Genome-wide association studies (GWAS) have identified numerous disease-associated variants; however, these variants have a minor effect on disease and explain only a small amount of the heritability of this complex disorder. The search for the missing heritability has shifted attention to rare variants, copy number variants, copy neutral variants and epigenetic modifications. Over 3,000 genes distributed across the human genome have been screened for association with AD during the past 30 years [1]. In the Alzgene database [39] there are 695 genes potentially associated with AD, of which the top ten are (in decreasing order of importance): APOE (19q13.2), BIN1 (2q14), CLU (8p21-p12), ABCA7 (19p13.3), CR1 (1q32), PICALM (11q14), MS4A6A (11q12.1), CD33 (19q13.3), MS4A4E (11q12.2), and CD2AP (6p12). Potentially defective genes associated with AD represent about 1.39% (35,252.69 Kb) of the human genome, which is integrated by 36,505 genes (3,095,677.41 Kb). The highest number of AD-related defective genes is concentrated on chromosomes 10 (5.41%; 7337.83 Kb), 21 (4.76%; 2,289,15 Kb), 7 (1.62%; 2,584.26 Kb), 2 (1.56%; 3,799.67 Kb), 19 (1.45%; 854.54 Kb), 9 (1.42%; 2,010.62 Kb), 15 (1.23%; 1,264.4 Kb), 17 (1.19%; 970.16 Kb), 12 (1.17%; 1,559.9 Kb), and 6 (1.15%; 1,968.22 Kb), with the highest proportion (related to the total number of genes mapped on a single chromosome) located on chromosome 10 and the lowest on chromosome Y [3].

The genetic and epigenetic defects identified in AD can be classified into 4 major categories: Mendelian mutations, susceptibility singlenucleotide polymorphisms (SNPs), mitochondrial DNA (mtDNA) mutations, and epigenetic changes. Mendelian mutations affect genes directly linked to AD, including 32 mutations in the amyloid beta precursor protein (APP) gene (21q21)(AD1); 165 mutations in the presenilin 1 (PSEN1) gene (14q24.3)(AD3); and 12 mutations in the presenilin 2 (PSEN2) gene (1q31-q42) (AD4) [1-3,34-36,40-43]. PSEN1 and PSEN2 are important determinants of γ-secretase activity responsible for proteolytic cleavage of APP and NOTCH receptor proteins. Mendelian mutations are very rare in AD (1:1000). Mutations in exons 16 and 17 of the APP gene appear with a frequency of 0.30% and 0.78%, respectively, in AD patients. Likewise, PSEN1, PSEN2, and microtubule-associated protein Tau (MAPT) (17q21.1) mutations are present in less than 2% of the cases. Mutations in these genes confer specific phenotypic profiles to patients with dementia: amyloidogenic pathology associated with APP, PSEN1 and PSEN2 mutations, and tauopathy associated with MAPT mutations representing the two major pathogenic hypotheses for AD [1-3,34-36,40-43]. Ten novel private pathogenic copy number variations (CNVs) in 10 early-onset familial Alzheimer’s disease (EO-FAD) families overlapping a set of genes (A2BP1, ABAT, CDH2, CRMP1, DMRT1, EPHA5, EPHA6, ERMP1, EVC, EVC2, FLJ35024 and VLDLR) have also been identified [44].

Multiple polymorphic risk variants can increase neuronal vulnerability to premature death. Among these susceptibility genes, the apolipoprotein E (APOE) gene (19q13.2)(AD2) is the most prevalent as a risk factor for AD, especially in those subjects harboring the APOE-4 allele, whereas carriers of the APOE-2 allele might be protected against dementia [1,3]. Polymorphic variants in other genes (GRB-associated binding protein 2 (GAB2) [45], TLR9 rs187084 variant homozygote GG [46], LRRK2 R1628P variant [47]) might be protective, as well.

APOE-related pathogenic mechanisms are also associated with brain aging and with the neuro pathological hallmarks of AD [1-3,34,35,40-43,48-50]. mtDNA damage may also contribute to increase brain vulnerability and neuro degeneration [51,52].

Epigenomics of Alzheimer’s disease

As a complex polygenic/multifactorial disorder, in which hundreds of polymorphic variants of risk might be involved, AD fulfills the “golden rule” of complex disorders, according to which the larger the number of genetic defects distributed in the human genome, the earlier the onset of the disease and the poorer its therapeutic response to conventional treatments; and the smaller the number of pathogenic SNPs, the later the onset of the disease, and the better the therapeutic response to different pharmacological interventions [1,3,48,50,53]; however, conventional genomics do not explain in full AD pathogenesis in which epigenetics may help to understand some enigmatic events. DNA methylation, histone modifications and chromatin remodeling and non-coding RNA dysregulation may contribute to AD pathology, although evidence is still very limited [9,15,16,54-56]. Pharmaceuticals, pesticides, air pollutants, industrial chemicals, heavy metals, hormones, nutrition, and behavior can change gene expression through a broad array of gene regulatory mechanisms. Mechanisms include regulation of gene translocation, histone modifications, DNA methylation, DNA repair, transcription, RNA stability, alternative RNA splicing, protein degradation, gene copy number, and transposon activation [57]. Genetic variation associated with different diseases interferes with microRNA-mediated regulation by creating, destroying, or modifying miRNA binding sites. miRNA-target variability is a ubiquitous phenomenon in the adult human brain, which may influence gene expression in physiological and pathological conditions. One of the major roles of lncRNAs in the nucleus is the regulation of gene expression at the transcriptional level via histone or DNA modification [58]. Epigenetic mechanisms and miRNAs have recently been shown to closely interact with each other, thereby creating reciprocal regulatory circuits, which appear to be disrupted in AD [59]. Brain hypoperfusionrelated changes in DNA methylation may also contribute to accelerate neuronal death. Short-term, sub-lethal hypoxia results in long-lasting changes to genome-wide DNA methylation status, and some of these changes can be highly correlated with transcriptional modulation in a number of genes involved in functional pathways [60]. Inflammatory mechanisms contribute substantially to secondary tissue injury after brain ischemia. Regulatory T cells (RTC) are endogenous modulators of postischemic neuroinflammation. HDACi, using trichostatin A, increases the number of RTC, boosts their immunosuppressive capacity and interleukin (IL)-10 expression, reduces infarct volumes and behavioral deficits after cortical brain ischemia, attenuates cerebral proinflammatory cytokine expression, and increases the number of brain-invading RTC. A similar effect is obtained using tubastatin, a specific inhibitor of HDAC6 and a key HDAC in Foxp3 regulation. The neuroprotective effect of HDACi depends on the presence of Foxp3+ RTC, and in vivo and in vitro studies show that the anti-inflammatory cytokine IL-10 was their main mediator [61].

Memory decline is a seminal symptom in dementia. Gene expression is required for long-lasting forms of memory. Epigenetic mechanisms do not only provide complexity in the protein regulatory complexes that control coordinate transcription for specific cell function, but the epigenome encodes critical information that integrates experience and cellular history for specific cell functions as well. Epigenetic mechanisms provide a unique mechanism of gene expression regulation for memory processes. Negative regulators of gene expression, such as HDACs, have powerful effects on the formation and persistence of memory. HDAC inhibition transforms a subthreshold learning event into robust long-term memory and generates a form of long-term memory that persists beyond the point at which normal long-term memory fails [62]. Whereas increments in histone acetylation have consistently been shown to favor learning and memory, a lack thereof has been causally implicated in cognitive impairments in neurodevelopmental disorders, neurodegeneration and aging. As histone acetylation and cognitive functions can be pharmacologically restored by histone deacetylase inhibitors, this epigenetic modification might constitute a molecular memory aid on the chromatin and a new template for therapeutic interventions against cognitive decline [63].

DNA methylation

DNA methylation is involved in memory processes: (i) hippocampal DNMT expression is up-regulated during consolidation of contextual fear memory; (ii) intra-hippocampal administration of DNMT inhibitors blocks this memory consolidation, and DNMTiinduced memory deficits can be overcome by pretreatment with HDAC inhibitors; (iii) rapid changes in DNA methylation at the time of learning provide bi-directional transcriptional regulation of memory promoting and suppressing genes; (iv) conditional knockout mice lacking both DNMT1 and DNMT3a forebrain expression display memory dysfunction and deficits in long-term plasticity in the hippocampus; (v) hippocampal learning triggers gene-specific hypermethylation in the cortex which persists for weeks; and (vi) DNA methylation can be both dynamic, supporting synaptic consolidation, and stable, supporting system consolidation [64].

Several pathogenic genes (APP, PS1, APOE, BACE, CLU) and many other AD-related susceptibility genes contain methylated CpG sites and a genome-wide decrease in DNA methylation has been reported in AD [9,55] (Table 1). The promoter region of the APP gene is hypomethylated, this contibuting to a potential enhancement of Aβ production; however, some authors have reported no relevant changes in APP methylation, with an epigenetic drift in AD samples [65]. Methylation status of repetitive elements (i.e. Alu, LINE-1 and SAT-α) is a major contributor of global DNA methylation patterns. The study of global DNA methylation levels for long interspersed nuclear element 1 (LINE-1) repetitive sequences in patients with AD and controls did not provide clear results. In one study, no differences in LINE-1 methylation levels were found between patients and controls [66]; whereas in another study, LINE-1 methylation was found increased in AD patients compared with healthy volunteers [67]. In AD, both hypomethylation and hypermethylation of specific genes have been reported [9] (Table 1). DNA methylation of the APP promoter was found to be decreased in the brain of autopsy cases older than 70 years of age as compared with younger cases [68]. The intracellular domain of APP (AICD) has emerged as a key epigenetic regulator of gene expression controlling a diverse range of genes, including APP itself, the amyloid-degrading enzyme neprilysin, and aquaporin-1 [69]. Abnormal processing of neuronal cell membrane APP is accompanied by elevated human serum and CSF levels of 24-hydroxycholesterol, an endogenous ligand of Liver X receptor (LXR-α). There is an epigenomic pathway that connects LXR-α activation with genes involved in the regulation of aberrant Aβ production, leading to the generation of toxic and inflammatory mediators responsible for neuronal death. LXR-α activation by its specific endogenous or exogenous ligands results in the overexpression of the PAR-4 gene and suppression of the AATF gene through its inherent capacity to regulate genes coding for SREBP and NF-κB. Overexpression of the PAR-4 gene is accompanied by aberrant Aβ production followed by ROS generation and subsequent neuronal death. Aβ-induced heme oxygenase-1 can ensure cholesterol-oxidation to provide endogenous ligands for the sustained activation of neuronal LXR-α-dependent epigenomic pathways, leading to neuronal death in AD [70].

Pathogenic genes Locus Promoter length (bp) 3'UTR length Defective protein Methylation
APOE   apolipoprotein E 19q13.32 996 -- apolipoprotein E Hypomethylated
APP
amyloid beta (A4) precursor protein
21q21.3 1086 1176 amyloid beta (A4) protein Hypomethylated
BACE1
beta site APP cleaving enzyme 1
11q23.2-q23.3 987 3994 beta-secretase 1 Hypomethylated
CREB
cAMP response element binding protein 1
2q33.3 1026 -- cAMP response element binding protein 1 Hypomethylated
MAPT   microtubule-associated protein tau 17q21.31 1094 -- microtubule-associated protein tau Hypermethylated
MTHFR   methylene Tetrahydropholate reductase 1p36.22 959 -- methylene tetrahydropholate reductase Hypermethylated
NCSTN   nicastrin 1q22-q23 922 766 nicastrin Hypermethylated
MME   Membrane metallo- endopeptidase 3q25.1-q25.2 972 3330 neprilysin Hypermethylated
PP2A     protein phosphatase 2 9q34 981 1598 serine/threonine-protein phosphatase 2A activator Hypomethylated
PSEN1     
presenilin 1
14q24.2 929 1198 presenilin 1 Hypomethylated
S100A2  
S100 calcium binding protein A2
1q21.3 902 400 protein S100-A2 Hypomethylated
SORBS3
  sorbin and SH3 domain containing 3
8p21.3 972 939 vinexin Hypermethylated
SPTBN4  spectrin beta nonerythrocytic 4 19q13.13 947 993 spectrin beta chain, non-erythrocytic 4 Hypermethylated
TBXA2R  thromboxane A2 receptor 19p13.3 983 1335 thromboxane A2 receptor Hypermethylated
TMEM59 transmembrane protein 59 1p32.3 1016 628 transmembrane protein 59 Hypomethylated

Table 1: Gene methylation patterns in Alzheimer’s disease.

Hyper phosphorylated tau is responsible for the formation of NFTs. Changes in methylation status differ among transcription factor binding sites of tau promoter. Binding sites for GCF (granulocyte chemotactic factor), responsible for repression of GC-rich promoters, were found to be hypo methylated, whereas binding sites for the transcriptional activator SP1 (specificity factor 1) were hyper methylated [71]. High levels of Hcy may induce tau hyper phosphorylation, NFT formation, and SP formation via inhibition of methyl transferases and hypomethylation of protein phosphatase 2A (PP2A), a dephosphorylating enzyme of phosphorylated tau [72].

Histone modifications

Histone modifications are present in AD [9,15,16,63,73]: (i) histone acetylation is reduced in AD brain tissues [74] and in AD transgenic models [63]; (ii) levels of HDAC6, a tau-interacting protein and a potential modulator of tau phosphorylation and accumulation, are increased in cortical and hippocampal regions in AD [75]; (iii) SIRT1 is decreased in the parietal cortex of AD patients, and the accumulation of Aβ and tau in AD brains might be related to the loss of SIRT1 [76], since SIRT1 may reduce Aβ production, activating the transcription of ADAM10 [77]; (iv) in the brains of twins discordant for AD, tri methylation of H3K9, a marker of gene silencing, and condensation of heterochromatin structure, are increased in the temporal cortex and hippocampus of the AD twin as compared to the twin devoid of AD neuropathology [78]; (v) phosphorylation of H3S10, a key regulator in chromatin compaction during cell division, is increased in the cytoplasm of hippocampal neurons in AD cases [79]; (vi) evidence of DNA damage, as reflected by phosphorylated H2AX at Ser139, is present in hippocampal astrocytes of AD patients [80]; (vii) long-term potentiation (LTP) and memory deficits in APP/PS1 transgenic mice might be mediated in part by decreased H4 acetylation; improving histone acetylation level restores learning after synaptic dysfunction [81]; (viii) acetylation of H3 and H4 is increased in 3xTg-AD neurons relative to non-transgenic neurons [82]; (ix) nuclear translocation of EP300 interacting inhibitor of differentiation 1 (EID1), a CBP/p300 inhibitory protein, is increased in the cortical neurons of AD patients, and overexpression of EID1 is reported to reduce hippocampal LTP and to impair cognitive function via inhibiting CBP/p300 acetyl trasferase activity and disrupting neuronal structure [83]; (x) memory formation leads to a transient increase in acetylation on lysine residues within H2B, H3, H4 [84,85]; (xi) inhibition of HDAC induces dendritic sprouting, increases synaptic number, and improves long-term memory [86]; (xii) overexpression of neuronal HDAC2 decreases dendritic spine density, synapse number, synaptic plasticity and memory formation, and HDAC2 deficiency increases synapse number and memory facilitation [87,88]; (xiii) HDAC4 is involved in learning and synaptic plasticity, and selective inhibition of HDAC4 activity may deteriorate learning and memory [89]; (xiv) treatment of hippocampal neurons with HDAC inhibitors facilitates Bdnf expression via hyper acetylation of histones at the Bdnf promoters [90,91]; (xv) histone(H3K4) methylation participates in the regulation of Bdnf expression and memory formation [92]; (xvi) histone methylation also facilitates memory consolidation coupled with histone acetylation; inhibition of HDACs with sodium butyrate (NaB) causes an increase in H3K4 trimethylation and a decrease in H3K9 dimethylation in the hippocampus after fear conditioning [92]; (xvii) histone H3 acetylation, methylation and phosphorylation is increased in the prefrontal cortex of Tg2576 mice, and histone H4 acetylation is increased in the hippocampal CA1 neurons of these transgenic mice [15,16,93].

Non-coding RNAs

miRNAs belong to the class of non-coding regulatory RNA molecules of ~22 nt length and are now recognized to regulate ~60% of all known genes through post-transcriptional gene silencing (RNA interference)(RNAi). Alterations in epigentically regulated miRNAs may contribute to the abnormal expression of pathogenic genes in AD [59,94]. Several lncRNAs are dysregulated in AD (Sox2OT, 1810014B01Rik, BC200, BACE1-AS, NAT-Rad18, 17A, GDNFOS), Parkinson’s disease (naPINK1, Sox2OT, 1810014B01Rik, BC200), and Huntington’s disease (HAR1F, HTTAS, DGCR5, NEAT1, TUG1) [94]. Examples of miRNAs directly linked to AD pathogenesis include miR-34a (1p36.22), miR-34b/c (11q23.1), miR-107 (10q23.31), miR- 124 (8p23.1/8p12.3/20q13.33), miR-125b (11q24.1/21q21.1), and miR-137 (1p21.3); and examples of epigenetically regulated miRNAs with targets linked to AD pathogenesis are let-7b (22q13.1), miR-9 (1q22/5q14.3/15q26.1), miR-132/212 (17p13.3), miR-146a (5q34), miR- 148a (7p15.2), miR-184 (15q25.1), and miR-200 (miR-200b/200a/429, 1p36.33; miR-200c/141, 12p13.31) [59].

miRNAs can be used as biomarkers to discriminate different disease forms, staging and progression, as well as prognosis [95]. A unique circulating 7-miRNA signature (hsa-let-7d-5p, hsa-let-7g-5p, hsa-miR- 15b-5p, hsa-miR-142-3p, hsa-miR-191-5p, hsa-miR-301a-3p and hsamiR- 545-3p) reported by Kumar et al. [95] in plasma, could distinguish AD patients from normal controls with >95% accuracy. Leidinger et al. [96] showed a novel miRNA-based signature for detecting AD from blood samples. Using this 12-miRNA signature, they differentiated between AD and controls with an accuracy of 93%, a specificity of 95% and a sensitivity of 92%. The differentiation of AD from other neurological diseases (MCI, multiple sclerosis, Parkinson disease, major depression, bipolar disorder and schizophrenia) was possible with accuracies between 74% and 78%. Alexandrov et al. [97] found increased levels of miRNA-9, miRNA-125b, miRNA-146a, miRNA-155 in the CSF and brain tissue-derived extracellular fluid from patients with AD, suggesting that these miRNAs might be involved in the modulation or proliferation of miRNA-triggered pathogenic signaling in AD brains.

AD-related SNPs interfere with miRNA gene regulation and affect AD susceptibility. The significant interactions include target SNPs present in seven genes related to AD prognosis with the miRNAs- miR- 214, -23a & -23b, -486-3p, -30e*, -143, -128, -27a &-27b, -324-5p and -422a. The dysregulated miRNA network contributes to the aberrant gene expression in AD [37,38,98].

Epigenetic Drugs

Epigenetic drugs (Tables 2 and 3) reverse epigenetic changes in gene expression and might open future avenues in AD therapeutics and other major problems of health [9,15,16,73,99-105]. Epigenetic effects are exerted by a variety of factors and evidence increases that common drugs may induce alterations in DNA methylation patterns or histone conformations. These effects occur via chemical structural interactions with epigenetic enzymes, through interactions with DNA repair mechanisms [106,107]. Several inhibitors of histone deacetylation and DNA methylation have been approved by the US FDA for hematological malignancies [15-17,99] (Table 2).

DNA methyltransferase inhibitors
Nucleoside analogs
5-Aza-2’-deoxycytidine (Decitabine)
5-Azacytidine (Azacitidine)
Small molecules
Hydralazine
Procainamide
RG108 [2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-(1H-indol-3-yl)propanoic acid])
Natural products
Curcumin derivatives
RG-108
SGI-1027
Psammaplins
Tea polyphenols
Epigallocatechin-3-gallate
Catechins
Catechin
Epicatechin
Bioflavonoids
Quercetin
Genistein
Fisetin
Antisense oligonucleotide inhibitors
ncRNAs (miRNAs)
Histone deacetylase (HDAC) inhibitors
Short-chain fatty acids
Sodium butyrate
Sodium phenyl butyrate
Valproic acid
Pivaloyloxymethyl butyrate (AN-9, Pivanex)
Hydroxamic acids
Suberoylanilide hydroxamic acid (SAHA, Vorinostat)
Oxamflatin
Pyroxamide
Trichostatin A (TSA)
m-Carboxycinnamic acid bis-hydroxamide (CBHA)
Derivatives of the marine sponge Psammaplysilla purpurea
NVP-LAQ824
NVP-LBH589
LBH-589 (Panobinostat)
ITF2357 (Givinostat)
PXD101 (Belinostat)
JHJ-26481585
CHR-3996
CHR-2845
PCI-24781
Cyclic peptides
Romidepsin (Depsipeptide, FR901228) < Apicidin
Cyclic hydroxamic acid-containing peptides (CHAPS)
Trapoxin A and B
Chlamydocin
HC toxin
Bacterial FK228
Benzamides
MS-275 (Entinostat)
CI-994
RGFP136
MGCD0103 (Mocetinostat)
Compound 60
Ketones
Trifluoromethyl ketone
Sirtuin modulators
Sirtuin inhibitors
Nicotinamide/niacinamide
Suramin
AGK-2
Sirtinol
Salermide
MS3
Splitomycin
Cambiol
SEN-196
Dihydrocoumarin
Tenovin
UVI5008
Sirtuin activators
Resveratrol
SRT-501
SRT-1460
SRT-1720
SRT-2183
GSK-184072
Quercetin
Piceatannol
Miscellaneous compounds
3-Deazaneplanocin A (DZNep)
Tubacin
EVP-0334
6-([18F]Fluoroacetamido)-1-hexanoicanilide
Quinazolin-4-one derivatives
(E)-3-(2-Ethyl-7-fluoro-4-oxo-3-phenethyl-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide
N-Hydroxy-3-(2-methyl-4-oxo-3-phenethyl-3,4-dihydro-quinazolin-7-yl)-acrylamide
Histone acetyltransferase modulators
Histone acetyltransferase inhibitors
Curcumin (Diferuloylmethane)
Lys-CoA
H3-CoA-20
Anacardic acid
Garcinol
Histone aceyltransferase activators
N-(4-Chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide
Pentadecylidenemalonate 1b (SPV-106)
Histone methyltransferase inhibitors
Lysine methyltransferase inhibitors
S-Adenosylmethionine (SAMe)
SAMe analogs
Chaetocin
BIX-01294
BIX-01338
UNC0224
EZH2 (KMT6) inhibitors
Deazaneplanocin A
Arginine methyltransferase inhibitors
AMI-1
Histone demethylase inhibitors
Lysine-specific demethylase 1 (LSD1) inhibitors
Tranylcypromine
Parnate
(S)-4-(2-(5-(Dimethylamino)naphthalene-1-sulfonamido)-2-phenylacetamido)-N-hydroxybenzamide (D17)
Non-coding RNAs
miRNAs
RNAi
Other potential epigenetic treatments
Small molecule inhibitors to chromatin-associated proteins
DOT1L histone methyltransferase inhibitors
EPZ004777
EPZ-5676
SGC0946
EZH2 histone methyltransferase inhibitors
GSK126
GSK343
EPZ005687
EPZ-6438
EI1
UNC1999
G9A histone methyltransferase inhibitors
BIX1294
UNC0321
UNC0638
NC0642
BRD4770
PRMT3 histone methyltransferase inhibitors
14u
PRMT4 (CARM1) histone methyltranferase inhibitors
17b
MethylGene
LSD1 histone demethylase inhibitors
Tranylcypromine
ORY-1001
BET histone demethylase inhibitors
JQ1
IBET762
IBET151
PFI-1
BAZ2B histone demethylase inhibitors
GSK2801
L3MBTL1 chromodomain inhibitors
UNC669
L3MBTL3 chromodomain
UNC1215
Bromodomain inhibitors
LP99
RVX-208
Chromodomain inhibitors

Table 2: Classification of selected epigenetic drugs.

Reducing the hyper methylation levels in some pathogenic genes may be an alternative therapy in AD, in addition to conventional treatments (cholinesterase inhibitors: donepezil, rivastigmine, galantamine; NMDA partial antagonists: memantine) (Table 4) or novel therapies (immune therapy/vaccination; secretase inhibitors; Aβ breakers; other unconventional treatments) [3]. Examples of DNMT inhibitors include (i) nucleoside analogs (5-aza-2’-deoxycytidine (Decitabine), 5-azacytidine (Azacitidine)), (ii) small molecules (hydralazine, procainamide, RG108 [2-(1,3-dioxo-1,3-dihydro 2H-isoindol-2-yl)-3-(1H-indol-3-yl)propanoic acid]), (iii) natural products (curcumin derivatives (RG-108, SGI-1027), psammaplins, tea polyphenols (epigallocatechin-3-gallate), catechins (catechin, epicatechin), bioflavonoids (quercetin, genistein, fisetin)), (iv) antisense oligonucleotide inhibitors (MG98), and (v) ncRNAs (miRNAs) [11,34,35] (Tables 2 and 3).

Drug Properties Pharmacogenetics
image Name: 5-Azacytidine, Azacitidine, Azacytidine, Ladakamycin, Vidaza, Mylosar, Azacitidinum, 5-AZAC
IUPAC Name: 4-Amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,3,5-triazin-2-one
Molecular Formula: C8H12N4O5
Molecular Weight: 244.20468
Category: Pyrimidine nucleoside cytidine analog
Mechanism: DNA methyltransferase inhibitor, Telomerase inhibitor
-Target:DNA (cytosine-5)-methyltransferase 1 (DNMT1)
-Interactions:Cytidine deaminase
Effect: Antineoplastic, Antimetabolite.Methylates CpG residues. Methylates hemimethylated DNA. Mediates transcriptional repression by direct binding to HDAC2
Pathogenic genes:
ALDH3A1, CDKN2A, MGMT, PLA2R1, RRM1, TNFRSF1B
Mechanistic genes:
ALDH1A1, DAPK1, DNMT1, DPYD, CDKN2A, MGMT, PLCB1
Metabolic genes:
Substrate: CDA, DCK, SLC28A1, SLC29A1, RRM1, RRM2, UCK1, UCK2
Inhibitor: CYP1A2 (weak), CYP2E1 (weak), DNMT1
Inducer: SULT1C2
Transporter genes:
SLC5A5,SLC28A1, SLC29A1
Pleiotropic genes:
BLK
image Name: Curcumin, Diferuloylmethane, Natural yellow 3, Turmeric yellow, Turmeric, Kacha haldi, Gelbwurz, Curcuma, Haldar, Souchet
IUPAC Name: (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione
Molecular Formula: C21H20O6
Molecular Weight: 368.3799
Category: Natural product (Curcuma longa)
Mechanism:Histone acetyltransferase (HAT) inhibitor
Effect: Non-steroidal anti-inflammatory agent; Antineoplastic; Antioxidant; Cognitive enhancer; Coloring agent; Enzyme inhibitor
Pathogenic genes:
BACE1, CCND1, CDH1, GSK3B, IL1A, IL6, JUN, MSR1, PSEN1, PTGS2, SNCA, SREBF1, TNF
Mechanistic genes:
AKT1,PRKAs, BACE1, CCND1, CDH1, CDKs, CRM1, CTNNB1, EGF, GSK3B, HDACs, HIF1A, IL1A, IL6, JUN, MMPs, MSR1, NFKB1, NOS2, PDGFRs, PSEN1, PTGS2, SNCA, SOCS1, SOCS3, SREBF1, STAT3, TNF, VEGFA
Metabolic genes:
Inhibitor: CYP2C8, CYP2C9, EP300
Inducer: CYP2C8, CYP2C9, CYP2D6, CYP3A4
Transporter genes:
ABCA1, SNCA
Pleiotropic genes:
CTNNB1, MSR1
image Name:Decitabine, 5-Aza-2'-deoxycytidine, Dacogen, Dezocitidine, 2'-Deoxy-5-azacytidine
IUPAC Name: 4-Amino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,3, 5-triazin-2-one
Molecular Formula: C8H12N4O4
Molecular Weight: 228.20528
Category: Nucleoside
Mechanism: DNA methyltransferase inhibitor
-Target:DNA (cytosine-5)-methyltransferase 1 (DNMT1)
-Interactions:Deoxycytidine kinase
Effect: Antineoplastic, Antimetabolite, Enzyme inhibitor, Teratogen
Pathogenic genes:
BRCA1, CDKN2B, DNMT3A, EGFR, FOS, MGMT, MLH1, MMP9, MYC, NOS3, NQO1, TP53, VHL
Mechanistic genes:
APAF1, BRCA1, CDKN2B, EGFR, ICAM1, MGMT, MLH1, MMP2, MMP9, MYC, NOS3, TIMP3, TP53, VHL
Metabolic genes:
Substrate: DCK, DNMT1, CDA, SLC29A1
Inhibitor: DNMT1, DNMT3B
Inducer: DPYD
Transporter genes:
ABCs, SLC15s, SLC22s, SLC28A1, SLC29As
Pleiotropic genes:
HBG1, NQO1, NTRK2, MMP2, MSH2
image Name: Entinostat, ms-275, 209783-80-2, SNDX-275, MS 275, MS-27-275, SNDX 275, Histone Deacetylase Inhibitor I, S1053_Selleck, MS 27-275
IUPAC Name: Pyridin-3-ylmethyl
N-[[4-[(2-aminophenyl)carbamoyl]phenyl]methyl]carbamate
Molecular Formula: C21H20N4O3
Molecular Weight: 376.4085
Category: Benzamide
Mechanism: Class I HDAC inhibitor (HDAC1, 2, 3)
Effect: Antineoplastic agent; Histone deacetylase inhibitor; Memory enhancer
Pathogenic genes:
CDH1
Mechanistic genes:
CDH1, HDAC1, HDAC2, HDAC3, KLRK1
Metabolic genes:
Inhibitor: HDAC1, HDAC2, HDAC3
Inducer: CYP19A1
image Name:Mocetinostat, MGCD0103, 726169-73-9, MGCD-0103, MGCD 0103, N-(2-Aminophenyl)-4-([[4-(pyridin-3-yl)pyrimidin-2 yl]amino]methyl)benzamide
IUPAC Name: N-(2-Aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amino]methyl] benzamide
Molecular Formula: C23H20N6O
Molecular Weight: 396.4445
Category: Benzamide
Mechanism: Class I HDAC inhibitor (HDAC1, 2, 3); Class IV HDAC inhibitor (HDAC11)
Effect: Antineoplastic agent; Histone deacetylase inhibitor
Pathogenic genes:
CDKN1A, CDKN2B, TNF
Mechanistic genes:
CDKN1A, CDKN2B, HDAC1, HDAC2, HDAC3, HDAC11, NFKB2, TNF
Metabolic genes:
Inhibitor: HDAC1, HDAC2, HDAC3,HDAC11
image Name: Panobinostat,LBH-589, 404950-80-7, LBH589, Faridak, NVP-LBH589, LBH 589, S1030_Selleck, AC1OCFY8, Panobinostat (LBH589)
IUPAC Name: (E)-N-hydroxy-3-[4-[[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl]phenyl]
prop-2-enamide
Molecular Formula: C21H23N3O2
Molecular Weight: 349.42622
Category: Hydroxamic acid
Mechanism: Class I HDAC inhibitor (HDAC1, 2, 3, 8); Class IIa HDAC inhibitor (HDAC4, 5, 7, 9); Class IIb HDAC inhibitor (HDAC6, 10); Class IV HDAC inhibitor (HDAC11); Pan-histone deacetylase inhibitor
Effect: Antineoplastic agent; Histone deacetylase inhibitor
Pathogenic genes:
CDKN1A, EGFR, IL6, RASSF1
Mechanistic genes:
AKT1, CDKN1A, DAPK1, DNMT1, EGFR, HDACs, HIST3H3, HIST4H4, HSP90As, IL6, IL10, IL12, IL23A, NFKB2, RASSF1,TLR3
Metabolic genes:
Substrate: CYP2C19, CYP2D6, CYP3A4
Inhibitor: AKT1, CYP19A1 (strong), HDACs
Pleiotropic genes:
IL10
image Name: Pivanex, AN-9, Pivalyloxymethyl butyrate, AN 9, 122110-53-6, BRN 4861411, ((2,2 Dimethylpropanoyl)oxy)methyl butanoate
IUPAC Name: Butanoyloxymethyl 2,2-dimethylpropanoate
Molecular Formula: C10H18O4
Molecular Weight: 202.24752
Category: Short-chain fatty acid
Mechanism: Class I HDAC inhibitor (HDAC1, 2, 3, 8)
Effect: Antineoplastic agent; Histone deacetylase inhibitor
Pathogenic genes:
BCL2, TP53
Mechanistic genes:
BAX, BCL2, BCR-ABL, HDACs, TP53
Metabolic genes:
Inhibitor: ABCB1, HDACs
Transporter genes:
ABCB1
image Name: Resveratrol, trans-resveratrol, 501-36-0, 3,4',5-Trihydroxystilbene, 3,4',5-Stilbenetriol, 3,5,4'-Trihydroxystilbene, Resvida, (E)-resveratrol
IUPAC Name: 5-[(E)-2-(4-Hydroxyphenyl)ethenyl]benzene-1,3-diol
Molecular Formula: C14H12O3
Molecular Weight: 228.24328
Category: Natural polyphenol
Mechanism:SIRT1 inducer/activator
Effect: Non-steroidal antiinflammatory agent; Anticarcinogenic; Antimutagenic; Antineoplastic; Antioxidant; Platelet aggregation inhibitor; Enzyme inhibitor; Lifespan extension; Memory improvement; Aβ decrease; Reduction of plaque formation
Pathogenic genes:
BCL2, CAV1, ESR1, ESR2, GRIN2B, NOS3, PTGS2, TNFRSF10A, TNFRSF10B
Mechanistic genes:
APP, ATF3, BAX, BAK1, BBC3, BCL2, BCL2L1, BCL2L11, BIRC5, CASP3, CAV1, CFTR, ESR1, ESR2, GRIN1, GRIN2B, HTR3A, NFKB1, NOS3, PMAIP1, PTGS1, PTGS2, SIRT1, SIRT3, SIRT5, SRC, TNFRSF10A, TNFRSF10B, TRPs
Metabolic genes:
Substrate: CYP1A1, CYP1A2, CYP1B1, CYP2E1, GSTP1, PTGS1, PTGS2
Inhibitor: CYP1A1, CYP1B1, CYP2C9, CYP2D6, CYP3A4, NQO2
Inducer: CYP1A2, SIRT1
Transporter genes:
ABCC1, ABCC2, ABCC3, ABCC4, ABCC8, ABCG1, ABCG2, CFTR, TRPs
image Name: Romidepsin, Depsipeptide, Chromadax, Istodax, Antibiotic FR 901228, FK228, FR 901228, FK-228, NSC 630176, NSC-630176
IUPAC Name: (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-di(propan-2-yl)-2-oxa-12,
13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,
22-pentone
Molecular Formula: C24H36N4O6S2
Molecular Weight: 540.69584
Category: Cyclic peptide
Mechanism:Class I HDAC inhibitor (HDAC1, 2, 3, 8); Class IIa HDAC inhibitor (HDAC4,5,7,9); Class IIb HDAC inhibitor (HDAC6, 10); Class IV HDAC inhibitor (HDAC11)
Effect: Antibiotic; Antineoplastic agent; Histone deacetylase inhibitor
Pathogenic genes:
BCL2, CCDN1, CDKN1A, MYC, NF2, RB1, ROS1, TNFSF10, VHL
Mechanistic genes:
BCL2, CCDN1, CDKN1A, FLT1, HDAC1, HDAC2, HDAC3, HDAC4, HSP90As, KDR, MYC, NF2, TNFSF10, VEGFs, VHL
Metabolic genes:
Substrate: ABCB1, ABCG2, CYP1A1 (minor), CYP2B6 (minor), CYP2C19 (minor), CYP3A4 (major), CYP3A5 (minor), NR1I3, SLCO1B3
Inhibitor: ABCB1, HDACs
Inducer: ABCG2
Transporter genes:
ABCB1, ABCC1, ABCG2, SLCO1B3
Pleiotropic genes:
CDH1, CDKN1A
image Name: S-Adenosylmethionine, Ademetionine, AdoMet, Donamet, S-adenosyl-L-methionine, SAMe, Methioninyladenylate, SAM-e, adenosylmethionine
IUPAC Name: (2S)-2-Amino-4-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl-methylsulfonio]butanoate
Molecular Formula: C15H22N6O5S
Molecular Weight: 398.43738
Category: Methyl radical donor
Mechanism:Histone methyltransferase inhibitor
Effect: Antineoplastic; Antiinflammatory; Memory enhancer;
PSEN1 repressor
Pathogenic genes:
AKT1, ERK, GNMT, MAT1A, PSEN1
Mechanistic genes:
AMD1, CAT, CBS, GCLC, GNMT, GSS, NOS2, ROS1, STAT1, TNF
Metabolic genes:
Substrate: COMT, GNMT, TPMT, SRM
Inhibitor: ABCB1, CYP2E1, NOS2
Transporter genes:
SLC25A26
Pleiotropic genes:
CAT, TNF
image Name: Sodium phenylbutyrate,Buphenyl, 4-Phenylbutiric acid, 4-Phenylbutanoic acid, Benzenebutanoic acid, Benzenebutyric acid, Butyric acid, 4-phenyl-, 1821-12-1, gamma-Phenylbutyric acid,
IUPAC Name: 4-Phenylbutanoic acid
Molecular Formula: C10H12O2
Molecular Weight: 164.20108
Category: Short-chain fatty acid
Mechanism: Class I HDAC inhibitor (HDAC1, 2, 3, 8); Class IIa inhibitor (HDAC4,5,7,9); Class IIb inhibitor (HDAC6,10)
Effect: Antineoplastic agent; Histone deacetylase inhibitor; Memory improvement; pTau decrease via GSK3β inactivation; C99 and Aβ decrease; Amyloid burden reduction
Pathogenic genes:
ARG1, ASS1, BCL2, CPS1, NAGS, OTC
Mechanistic genes:
BCL2, BDNF, EDN1, HDACs, HSPA8, ICAM1, NFKB2, NT3, VCAM1
Metabolic genes:
Inhibitor: HDACs
Inducer: ARG1, CFTR, CYP2B6, NFKB2
Transporter genes:
CFTR
Pleiotropic genes:
ASL, BDNF, VCAM1
image Name: Suramin, Naphuride, Germanin, Naganol, Belganyl, Fourneau, Farma, Antrypol, Suramine, Naganin
IUPAC Name: 8-[[4-methyl-3-[[3-[[3-[[2-methyl-5-[(4,6,
8-trisulfonaphthalen-1-yl)carbamoyl]phenyl]carbamoyl]phenyl]
carbamoylamino]benzoyl]amino]benzoyl]amino]naphthalene-1,3,5-trisulfonic acid
Molecular Formula: C51H40N6O23S6
Molecular Weight: 1297.2797
Category: Polyanionic compound
Mechanism: Class III HDAC/Sirtuin inhibitor (SIRT1-3)
Effect:Antineoplastic Agent; Trypanocidal Agent; Antiparasitic; Antinematodal (African trypanosomiasis, Onchocerca); Sirtuin inhibitor
Mechanistic genes:
FSHR, IL10, P2RY2, PDGFRB, RYR1, SIRT1,SIRT2, SIRT3, SIRT5
Metabolic genes:
Inhibitor: SIRT1, SIRT2, SIRT3
image Name:Trichostatin A,58880-19-6, TSA, Trichostatin A (TSA), CHEBI:46024, TSA; 2,4-Heptadienamide, 7-(4-(dimethylamino)phenyl)-N-hydroxy-4,6-dimethyl-7-oxo-
7-(4-(Dimethylamino)phenyl)-N-hydroxy-4,6-dimethyl-7-oxo-2,4-heptadienamide; [R-(E,E)]-7-[4-(Dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxo-2,4-heptadienamide
IUPAC Name: (2E,4E,6R)-7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4-dienamide
Molecular Formula: C17H22N2O3
Molecular Weight: 302.36818
Category: Hydroxamic acid
Mechanism: Class I HDAC inhibitor (HDAC1, 2, 3); Class IIa HDAC inhibitor (HDAC4, 7, 9); Class IIb inhibitor (HDAC6)
Effect: Antifungal agent; Antibacterial agent; Histone deacetylase inhibitor; Protein synthesis inhibitor; Antineoplastic; Memory improvement; Rescue of CA3-CA1 LTP in APP/PS1 transgenic models
Pathogenic genes:
BCL2
Mechanistic genes:
BCL2, HDACs, IL8, IL12A,IL12B, NFKB2, RARB
Metabolic genes:
Substrate: CYP3A4 (mayor)
Inhibitor: HDACs
Inducer: CYP1A1, CYP1B1, CYP2B6, CYP2E1, CYP7A1, SLC19A3
Transporter genes:
SLC19A3
image Name:Valproic Acid, 2-Propylpentanoic acid, Depakene, Depakine, Ergenyl, Dipropylacetic acid, Mylproin, Convulex, Myproic Acid
IUPAC Name: 2-Propylpentanoic acid
Molecular Formula: C8H16O2
Molecular Weight: 144.21144
Category: Short-chain fatty acid
Mechanism: Class I HDAC inhibitor (HDAC1, 2, 3, 8)
Effect: Anticonvulsant; Mood stabilizer; Antimanic agent; Enzyme inhibitor; Histone deacetylase inhibitor; GABA modulator; Memory improvement; Aβ and pTau decrease; CDK5 inactivation
Pathogenic genes:
CREB1, IL6, LEP, SCN2A, TGFB1, TNF, TRNK
Mechanistic genes:
ABAT, CDK5, GSK3B, HDAC1, HDAC2, HDAC3, HDAC8, HDAC9, LEP, LEPR, SCNs, SMN2
Metabolic genes:
Substrate: ABCB1, CYP1A1 (minor), CYP2A6 (major), CYP2B6 (minor), CYP2C9 (major), CYP2C19 (minor), CYP2E1 (minor), CYP3A4 (minor), CYP4B1 (major), CYP4F2 (minor), UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7
Inhibitor: ABCB1, ACADSB, AKR1A1, CYP2A6 (moderate), CYP2C9 (strong), CYP2C19 (moderate), CYP2D6 (weak), CYP3A4 (moderate), HDAC1, HDAC2, HDAC3, HDAC8, HDAC9, UGT1A9, UGT2B1, UGT2B7
Inducer: ABCB1, AKR1C4, CASR, CYP2A6, CYP2B6, CYP3A4, CYP7A1, MAOA, NR1I2, SLC5A5, SLC6A2, SLC12A3, SLC22A16
Transporter genes:
ABCB1, ABCC2, ABCG1, ABCG2, SCNs, SLC5A5, SLC6A2, SLC12A3, SLC22A16
Pleiotropic genes:
ABL2, AGPAT2, ASL, ASS1, CDK4, CHRNA1, COL1A1, CPS1, CPT1A, DRD4, FMR1, FOS, HBB, HFE, HLA-A, HLA-B, ICAM1, IFNG, IL6, IL10, LEPR, NAGS, NR3C1, OTC, PTGES, STAT3, TGFB1, TNF, TP53.
image Name: Vorinostat, Suberoylanilide hydroxamic acid(SAHA), Zolinza, Suberanilohydroxamic acid, 149647-78-9, N-hydroxy-N'-phenyloctanediamide, SAHA cpd
IUPAC Name: N'-Hydroxy-N-phenyloctanediamide
Molecular Formula: C14H20N2O3
Molecular Weight: 264.3202
Category: Hydroxamic acid
Mechanism: Class I HDAC inhibitor (HDAC1, 2, 3, 8)
Class IIb inhibitor (HDAC6)
Effect: Antineoplastic, Memory improvement
Pathogenic genes:
BIRC3, CCND1, CDKN1A, CFLAR, CYP19A1, ERBB2, ERBB3, EGFR, RB1, TP53, TNF
Mechanistic genes:
CDKN1A, EGFR, ERBB2, ERBB3, STATs, TYMS, VEGFs
Metabolic genes:
Substrate: CYP2A6 (minor), CYP2C9 (minor), CYP2C19 (major), CYP2D6 (minor), CYP3A4 (major)
Inhibitor: HDAC1, HDAC2, HDAC3, HDAC6
Inducer: CYP1A1, CYP1A2, CYP1B1
Pleiotropic genes:
ALPs, TNF, TYMS

Table 3: Pharmacological profile and pharmacogenetics of selected epigenetic drugs.

Drug Properties Pharmacogenetics
image Name: Donepezil hydrochloride, Aricept, 120011-70-3, Donepezil HCl, BNAG, E-2020, E2020
IUPAC Name: 2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one;hydrochloride
Molecular Formula: C24H30ClNO3
Molecular Weight: 415.9529 g/mol
Category: Cholinesterase inhibitor
Mechanism: Centrally active, reversible acetylcholinesterase inhibitor; increases the acetylcholine available for synaptic transmission in the CNS
Effect: Nootropic agent, cholinesterase inhibitor, parasympathomimetic effect
Pathogenic genes: APOE, CHAT
Mechanistic genes: CHAT, ACHE, BCHE
Drug metabolism-related genes:
- Substrate: CYP2D6 (major), CYP3A4 (major), UGTsACHE
- Inhibitor: ACHE, BCHE
Transporter genes: ABCB1
image Name: Galantamine hydrobromide, Galanthamine hydrobromide, 1953-04-4, Nivalin, Razadyne, UNII-MJ4PTD2VVW, Nivaline
IUPAC Name: (1S,12S,14R)-9-methoxy-4-methyl-11-oxa-4-azatetracyclo[8.6.1.0^{1,12}.0^{6,17}]heptadeca-6,8,10(17),15-tetraen-14-ol
Molecular Formula: C17H22BrNO3
Molecular Weight: 368.26548 g/mol
Category: Cholinesterase inhibitor
Mechanism: Reversible and competitive acetylcholinesterase inhibition leading to an increased concentration of acetylcholine at cholinergic synapses; modulates nicotinic acetylcholine receptor; may increase glutamate and serotonin levels
Effect: Nootropic agent, cholinesterase inhibitor, parasympathomimetic effect
Pathogenic genes: APOE, APP
Mechanisticgenes: ACHE, BCHE, CHRNA4, CHRNA7, CHRNB2
Drug metabolism-related genes:
- Substrate: CYP2D6 (major), CYP3A4 (major), UGT1A1
- Inhibitor: ACHE, BCHE
image Name: Memantine Hydrochloride, 41100-52-1, Namenda, Memantine HCL, Axura, 3,5-Dimethyl-1-adamantanamine hydrochloride, 3,5-dimethyladamantan-1-amine hydrochloride
IUPAC Name: 3,5-dimethyladamantan-1-amine;hydrochloride
Molecular Formula: C12H22ClN
Molecular Weight: 215.76278 g/mol
Category: N-Methyl-D-Aspartate receptor antagonist
Mechanism: Binds preferentially to NMDA receptor-operated cation channels; may act by blocking actions of glutamate, mediated in part by NMDA receptors
Effect: Dopamine agent, antiparkinson agent, excitatory amino acid antagonist, antidyskinetic
Pathogenic genes: APOE, MAPT, PSEN1
Mechanistic genes: CHRFAM7A, DLGAP1, FOS, GRIN2A, GRIN2B, GRIN3A, HOMER1, HTR3A
Drug metabolism-related genes:
-Inhibitor: CYP1A2 (weak), CYP2A6 (weak), CYP2B6 (strong), CYP2C9 (weak), CYP2C19 (weak), CYP2D6 (strong), CYP2E1 (weak), CYP3A4 (weak), NR1I2
Transporter genes: NR1I2
Pleiotropic genes: APOE, MAPT, MT-TK, PSEN1
image Name: Rivastigmine tartrate, 129101-54-8, SDZ-ENA 713, Rivastigmine hydrogentartrate, Rivastigmine Hydrogen Tartrate, ENA 713, ENA-713
IUPAC Name: (2R,3R)-2,3-dihydroxybutanedioic acid;[3-[(1S)-1-(dimethylamino)ethyl]phenyl] N-ethyl-N-methylcarbamate
Molecular Formula: C18H28N2O8
Molecular Weight: 400.42352 g/mol
Category: Cholinesterase inhibitor
Mechanism: Increases acetylcholine in CNS through reversible inhibition of its hydrolysis by cholinesterase
Effect: Neuroprotective agent, cholinesterase inhibitor, cholinergic agent
Pathogenic genes: APOE, APP, CHAT
Mechanistic genes: ACHE, BCHE, CHAT, CHRNA4, CHRNB2
Drug metabolism-related genes:
-Inhibitor: ACHE, BCHE
Pleiotropic genes: APOE, MAPT
image Name:Tacrine Hydrochloride, Tacrine HCl, 1684-40-8, Hydroaminacrine, tacrine.HCl, 9-AMINO-1,2,3,4-TETRAHYDROACRIDINE HYDROCHLORIDE, Tenakrin
IUPAC Name: 1,2,3,4-tetrahydroacridin-9-amine;hydrochloride
Molecular Formula: C13H15ClN2
Molecular Weight: 234.7246 g/mol
Category: Cholinesterase inhibitor
Mechanism: Elevates acetylcholine in cerebral cortex by slowing degradation of acetylcholine
Effect: Nootropic agent, cholinesterase inhibitor, Parasympathomimetic effect
Pathogenic genes: APOE
Mechanistic genes: ACHE, BCHE, CHRNA4, CHRNB2
Drug metabolism-related genes:
-Substrate: CYP1A2 (major), CYP2D6 (minor), CYP3A4 (major)
-Inhibitor: ACHE, BCHE, CYP1A2 (weak)
Transporter genes: SCN1A
Pleiotropic genes: APOE, CES1, GSTM1, GSTT1, LEPR, MTHFR

Table 4: Pharmacological properties and pharmacogenomics of conventional anti-dementia drugs

The structural classification of HDAC inhibitors differentiates several classes: (i) short-chain fatty acids (sodium butfyrate, sodium phenyl butyrate, valproic acid, pivaloyloxymethyl butyrate (AN-9, Pivanex))(selective inhibitors of class I HDACs); (ii) hydroxamic acids (suberoylanilide hydroxamic acid (SAHA, Vorinostat), oxamflatin, pyroxamide, trichostatin A (TSA), m-carboxycinnamic acid bis-hydroxamide (CBHA), derivatives of the marine sponge Psammaplysilla purpurea (NVP-LAQ824, NVP-LBH589), LBH-589 (Panobinostat), ITF2357 (Givinostat), PXD101 (Belinostat), CHR- 3996, CHR-2845, PCI-24781)(inhibitors of class I and II HDACs); (iii) cyclic peptides (depsipeptide FR901228, romidepsin; apicidin, cyclic hydroxamic acid-containing peptides (CHAPS), cyclic tetrapetides trapoxin A and B with the epoxyketone-containing amino acid (2S,9S)- 2-amino-8-0xo-9,10-epoxy-decanoyl (Aoe), chlamydocin, HC toxin, bacterial FK228)(class I HDAC inhibitors); (iv) benzamides (MS- 275 (Entinostat), CI-994, RGFP136, MGCD0103 (Mocetinostat)) (class I HDAC inhibitors; selective HDAC1 and HDAC3 inhibitors); (v) ketones (trifluoromethyl ketone); (vi) sirtuin inhibitors (Class III HDAC inhibitors)(nicotinamide/niacinamide, suramin); and (vii) miscellaneous compounds (MGCD-0103, natural bioproducts) [15- 17,101] (Tables 2 and 3).

miRNAs exert regulatory control over mRNA stability and translation and may contribute to local and activity-dependent posttranscriptional control of synapse-associated mRNAs. miRNAs are small non-coding RNA regulators of protein synthesis that are essential for normal brain development and function. Their profiles are significantly altered in AD. miR-9 and -181c are down-regulated by Aβ in hippocampal cultures. The Aβ precursor protein APP itself is a target of miRNA regulation. The 3’ untranslated regions (3’ UTRs) of TGFBI, TRIM2, SIRT1 and BTBD3 are repressed by miR-9 and -181c, either alone or in combination. miRNA are integral components of the APP regulatory framework and potential targets for future AD therapeutics. Cohen et al. found a developmentally and activityregulated miRNA (miR-485) that controls dendritic spine number and synapse formation in an activity-dependent homeostatic manner. Many plasticity-associated genes contain predicted miR-485 binding sites. The presynaptic protein SV2A is a target of miR-485. miR-485 negatively regulates dendritic spine density, postsynaptic density 95 (PSD-95) clustering, and surface expression of GluR2. miR-485 overexpression reduced spontaneous synaptic responses and transmitter release. miRNA-485 and the presynaptic protein SV2A regulate homeostatic plasticity and CNS development, and their dysfunction might have possible implications in AD.

RNA interference (RNAi) technology may potentially be able to control AD, inhibiting the protein expression of specific genes by activating a sequence-specific RNA degradation process [108]. Short interfering nucleic acid (siNA), siRNA, dsRNA, miRNA and short hairpin RNA (shRNA) are capable of mediating RNA interference (RNAi) against BACE, APP, PS-1 and PS-2 gene expression [9]. RNAi-based treatments represent a promising therapeutic strategy for AD and other complex disorders. miRNA mimics, analogs of miRNA precursors, and anti-miRNAs are being explored as candidate therapeutic interventions for AD. Overexpression of miR-124 and miR- 195 may reduce Aβ levels by targeting BACE1 [109,110].

Pharmacoepigenomics

Pharmacogenomics account for 30-90% variability in pharmacokinetics and pharmacodynamics; however, pharmacogenetics alone does not predict all phenotypic variations in drug response. Individual differences in drug response are associated with genetic and epigenetic variability and disease determinants [111,112]. The genes involved in the pharmacogenomic response to drugs fall into five major categories: (i) genes associated with disease pathogenesis; (ii) genes associated with the mechanism of action of drugs (enzymes, receptors, transmitters, messengers); (iii) genes associated with drug metabolism: (a) phase I reaction enzymes: alcohol dehydrogenases, aldehyde dehydrogenases, aldo-keto reductases, amine oxidases, carbonyl reductases, cytidine deaminase, cytochrome P450 enzyme family, cytochrome b5 reductase, dihydroprimidine dehydrogenase, esterases, epoxidases, flavin-containing monooxygenases, glutathione reductase/peroxidases, short-chain dehydrogenases/reductases, superoxide dismutases, and xanthine dehydrogenase; and (b): phase II reaction enzymes: amino acid transferases, dehydrogenases, esterases, glucuronosyl transferases, glutathione transferases, methyl transferases, N-acetyl transferases, thioltransferase, and sulfotransferases; (iv) genes associated with drug transporters: ABC genes, especially ABCB1 (ATPbinding cassette, subfamily B, member 1; P-glycoprotein-1, P-gp1; Multidrug Resistance 1, MDR1), ABCC1, ABCG2 (White1), genes of the solute carrier superfamily (SLC) and solute carrier organic (SLCO) transporter family, responsible for the transport of multiple endogenous and exogenous compounds, including folate (SLC19A1), urea (SLC14A1, SLC14A2), monoamines (SLC29A4, SLC22A3), aminoacids (SLC1A5, SLC3A1, SLC7A3, SLC7A9, SLC38A1, SLC38A4, SLC38A5, SLC38A7, SLC43A2, SLC45A1), nucleotides (SLC29A2, SLC29A3), fatty acids (SLC27A1-6), neurotransmitters (SLC6A2 (noradrenaline transporter), SLC6A3 (dopamine transporter), SLC6A4 (serotonin transporter, SERT), SLC6A5, SLC6A6, SLC6A9, SLC6A11, SLC6A12, SLC6A14, SLC6A15, SLC6A16, SLC6A17, SLC6A18, SLC6A19), glutamate (SLC1A6, SLC1A7), and others); and (v) pleiotropic genes involved in multifaceted cascades and metabolic reactions [3,113-117] (Tables 3 and 4).

Epigenetic regulation is responsible for the tissue-specific expression of genes involved in pharmacogenetic processes, and epigenetics plays a key role in the development of drug resistance. Epigenetic changes affect cytochrome P450 enzyme expression, major transporter function, and nuclear receptor interactions [114-117]. Although this is a still poorly explored field, epigenetic regulation of genes encoding drug-metabolizing enzymes (CYP1A1, 1A2, 1B1, 1A6, 2A13, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 2J2, 2F1, 2R1, 2S1, 2W1, 3A4, 3A5, 3A7, 3A43, UGT1, GSTP1), drug transporters (ABCB1/MDR1/P-gp, ABCC1/MRP1, ABCC11/MRP8, ABCG2/BCRP, SLC19A1, SLC22A8), and nuclear receptors (RARB2, ESR1, NR1I2, HNF41) has been documented in pioneering studies of pharmacoepigenetics [111-118] (Table 5).

Category Gene Locus Promoter length (bp) Pathology Methylation
Phase I Drug Metabolism Genes ALDH1A2 15q21.3 982 prostate cancer Hypermethylated
CYP1A1 15q24.1 1200 head and neck cancer
prostate cancer fetal growth restriction (toxics) smoking-related
Hypermethylated Hypermethylated Hypomethylated Hypomethylated
CYP1B1 2p22.2 1193 colorectal cancer
prostate cancer hepatoma cell lines
breast cancer
Hypermethylated Hypomethylated Hypermethylated Hypermethylated
CYP24A1 20q13 945 vitamin D deficiency
tumor-derived endothelial cells
Hypermethylated Hypermethylated
CYP27B1 12q14.1 917 breast cancer choriocarcinoma lymphoma and leukemia Hypermethylated Hypermethylated Hypermethylated
CYP2A13 19q13.2 928 head and neck cancer Hypermethylated
CYP2C19 10q24 1048 Drug resistance Hypermethylated
CYP2E1 10q26.3 918 Parkinson's disease
toluene exposure
Hypomethylated Hypomethylated
CYP2R1 11p15.2 1026 vitamin D deficiency Hypermethylated
CYP2W1 7p22.3 934 colorectal cancer bladder, breast, thyroid cancer liver, stomach cancer Hypomethylated Hypomethylated Hypomethylated
CYP7B1 8q21.3 1052 prostate cancer Hypomethylated
Phase II Drug Metabolism Genes GSTM1 1p13.3 900 head and neck cancer Hypermethylated
GSTP1 11q13 958 toluene exposure
hepatoma cells
prostate cancer
breast cancer
Hypomethylated Hypermethylated Hypermethylated Hypomethylated
NAT1 8p22 2132 breast cancer Hypomethylated
SULT1A1 16p12.1 1086 breast cancer Hypermethylated
UGT3A2 5p13.2 1076 hepatoma cells Hypermethylated
Phase III Transporter Genes ABCA7 19p13.3 967 Alzheimer's disease Hypomethylated
ABCB1 7q21.12 906 breast cancer resistance to chemotherapy Hypermethylated Hypomethylated
ABCC6 16p13.1 975 bladder cancer Hypermethylated
ABCG2 4q22 1199 T-cell acute lymphoblastic leukemia cell lines Hypomethylated
SLC19A1 21q22.3 1040 CNS lymphomas Hypomethylated
SLC22A3 6q25.3 1034 prostate cancer Hypermethylated
SLC24A4 14q32.12 1029 Alzheimer's disease Hypomethylated

Table 5: Methylation patterns in genes associated with Phase I-II drug metabolism and transporters.

Epigenetic modifications are also associated with drug resistance [116-119]. The acquisition of drug resistance is tightly regulated by post-transcriptional regulators such as RNA-binding proteins (RBPs) and miRNAs, which change the stability and translation of mRNA encoding factors involved in cell survival, proliferation, epithelialmesenchymal transition, and drug metabolism [116,117].

Conclusions

(i) Epigenetic changes (DNA methylation, histone remodeling, miRNA regulation) are common phenomena in brain disorders.

(ii) Genes associated with the pathogenesis of neurodegeneration in Alzheimer’s disease exhibit epigenetic changes suggesting that epigenetics might contribute to the pathogenesis of dementia.

(iii) DNA methylation influence phenotype differences, such as susceptibility to certain diseases and pathogens, and response to drugs and xenobiotic agents.

(iv) Epigenetic modifications are associated with drug resistance.

(v) Epigenetic modifications are reversible and can be potentially targeted by pharmacological and dietary interventions.

(vi) Epigenetic drugs can reverse epigenetic changes in gene expression and might open future avenues for the treatment of brain disorders.

(vii) A series of epigenetic drugs have been developed, including DNA methyltransferase inhibitors (nucleoside analogs, small molecules, bioproducts, antisense oligonucleotides, miRNAs), histone deacetylase inhibitors (short-chain fatty acids, hydroxamic acids, cyclic peptides, benzamides, ketones, sirtuin inhibitors, sirtuin activators), histone acetyltransferase modulators, histone methyltransferase inhibitors, histone demethylase inhibitors, and non-coding RNAs (miRNAs) with potential effects against major problems of health. Some epigenetic drugs have been approved for the treatment of different modalities of cancer.

(viii) Pharmacoepigenomics deals with the influence that epigenetic alterations may exert on genes involved in the pharmacogenomic network responsible for the pharmacokinetics and pharmacodynamics of drugs (efficacy and safety), as well as the effects that drugs may have on the epigenetic machinery.

(ix) Genes involved in the pharmacogenomic process include pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes which are susceptible to epigenetic modifications leading to altered expression of proteins and enzymes, with the consequent effects on the therapeutic outcome.

(x) Although the information available at present on the pharmacoepigenomics of most drugs is very limited, growing evidence indicates that epigenetic changes are determinant in the pathogenesis of many medical conditions and in drug response and drug resistance; consequently, pharmacoepigenetic studies should be incorporated in the future as routine procedures for the proper evaluation of efficacy and safety issues in drug development and clinical trials.

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