Table 4.
Epigenetic dysregulation in Alzheimer’s disease: DNA (de)methylation.
| Gene | Regulation | Epigenetic modification | Observed in | Sample size | Approach | Methods | Reference |
|---|---|---|---|---|---|---|---|
| APP | ↓ | Methylation (APP gene promoter region) | AD patients | 16 1 |
Targeted (18 loci) Targeted (1 locus) |
BS Southern Blot |
Tohgi et al., 1999 West et al., 1995 |
| ≠ | Methylation (CpG sites in and close to the promoter region) |
AD patients | AD Stages I to II (n=17), AD Stages III to IV (n=15), AD Stages V to VI (n=12) |
Targeted (6 loci) |
BS |
Barrachina and Ferrer, 2009, Fuso et al., 2005 |
|
| PS | ≠ | Methylation (CpG sites in and close to the promoter region) |
SK-N-SH and SK-N-BE cell lines |
- | Targeted (5 loci) |
HPLC/Nucleic acid analysis |
Fuso et al., 2005 |
| BACE | ≠ | Methylation (CpG sites in and close to the promoter region) |
SK-N-SH and SK-N-BE cell lines |
- | Targeted (5 loci) |
HPLC/Nucleic acid analysis |
|
| ↓ | Expression due to folate deptivation-induced global DNA hypomethylation |
SK-N-SH and SK-N-BE cell lines |
- | Targeted (5 loci) |
HPLC/Nucleic acid analysis |
||
| PS1 | ≠ | Methylation (promoter region) | AD patients | 24 | Targeted (12 loci) |
BS | Wang et al., 2008b |
| ↑ | Expression due to folate deptivation -induced global DNA hypomethylation |
SK-N-SH and SK-N-BE cell lines |
- | Targeted (5 loci) |
HPLC/Nucleic acid analysis |
Fuso et al., 2005 | |
| APOE | ≠ | Methylation (promoter region) |
AD patients | 24 | Targeted (12 loci) |
BS, MALDI | Wang et al., 2008b |
| MTHFR | ≠ | Methylation (promoter region) |
AD patients (prefrontal cortex, peripheral lymphocytes) |
24 | Targeted (12 loci) |
BS | |
| ↑ | Methylation | ||||||
| DNMT1 | ≠ | Methylation (promoter region) |
AD patients | 24 | Targeted (12 loci) |
BS | |
| PP2A | ↓ | Inhibition of methylation due to increase of Hγ levels |
N2a cells, AD mouse model (APP/PS1) |
-, N.S. | Targeted (1 locus) |
IHC | Zhou et al., 2008 |
|
SORBS3 S100A2 |
↑ ↓ |
Methylation | AD patients | 18 | Targeted (50 loci) |
BS, MS-PCR | Siegmund et al., 2007 |
| NEP | ↑ | Methylation | CEC cell line exposed to Aβ |
- | Targeted (1 locus) |
MS-PCR | Chen et al., 2009 |
| SP1 | ↑ | Methylation (activator binding site) |
Human (cerebral cortex) |
16 | Targeted (18 loci) |
BS | Tohgi et al., 1999 |
| GCF | ↓ | Methylation (repressor binding site) |
Human (cerebral cortex) |
16 | Targeted (18 loci) |
BS | Tohgi et al., 1999 |
| APOE | ↑ | Methylation (CpG island located at the 3’ end) |
AD patients (postmortem) |
24 | Targeted (12 loci) |
BS | Wang et al., 2008b |
| COX-2 | ↓ | Methylation (promoter region) |
AD patients (frontal cortex) |
10 | Targeted (8 loci) |
Promoter region-specific CpG methylation assay |
Rao et al., 2012 |
| NF-kB | ↓ | Methylation (promoter region) |
|||||
| BDNF | ↑ | Methylation (promoter region) |
|||||
| CREB | ↑ | Methylation (promoter region) | |||||
| LINE-1 | ↑ | Methylation | AD patients (blood) | 43 | Targeted (3 loci) |
BS, PCR, pyrosequencing |
Bollati et al., 2011 |
| ANK1 | ↑↑ | Methylation | AD patients (EC, superior temporal cortex, PFC) |
62, 122, 144 | Genome-wide | 450K BeadChip | Lunnon et al., 2014 |
| Protein/(hydroxy) methylated base |
Regulation | Modification in | Observed in | Sample size | Methods | Reference |
| 5-hmC | ↓ | Expression | AD mouse model (APP/PS1; hippocampus) AD patients (EC, cerebellum) |
10 10 |
IHC IHC |
Chouliaras et al., 2013a Chouliaras et al., 2013a |
| 5-mC, 5-hmC | ↑ | AD patients (MGF, MTG, hippocampus) | 7 late-stage AD | IHC | Bradley-Whitman and | |
| 5 preclinical AD | Lovell, 2013 | |||||
| 13 MGF 29 MTG | IHC | Coppieters et al., 2014 | ||||
| 5-fC, 5-caC | ↓ | AD patients (hippocampus) | 7 late-stage AD | IHC | Bradley-Whitman and | |
| 5 preclinical AD | Lovell, 2013 | |||||
| DNMT3a | ↓ | AD mouse model (APP/PS1; hippocampus) | 10 | IHC | Chouliaras et al., 2013a | |
| AD patients | 10 | IHC | Chouliaras et al., 2013a | |||
| DNMT3a2 | ↓ | Mice (12 months old) | 15 | IHC | Oliveira et al., 2012 | |
| TET1 | ↑ | AD patients (hippocampus) | 7 late-stage AD | IHC | Bradley-Whitman and | |
| 5 preclinical AD | Lovell, 2013 | |||||
indicates increased expression levels,
indicates decreased expression levels, and
indicates altered expression, not further specified.
Abbreviations: 450K BeadChip, Illumina Infinium HumanMethylation 450K BeadChip; 5-caC, 5-carboxylcytosine; 5-fC, 5-formylcytosine; 5-hmC, 5-hydroxymethylcytosine; 5-mC, 5-methylcytosine; AD, Alzheimer’s disease; APOE, apolipoprotein E; APP, amyloid β precursor protein; BACE, β-secretase; BDNF, brain-derived neurotrophic factor; CEC, cerebral endothelial cell, COX-2, cyclooxygenase-2; CpG, cytosine-phosphate-guanine; CREB, cyclic adenosine monophosphate response element-bindingprotein; DNMT, DNA methyltransferase; EC, entorhinal cortex; GCF, granulocyte chemotactic factor; LINE-1,longinterspersed element 1; ANK1,ankyrin 1; MALDI, matrix-assisted laserdesorption/ionization; MFG, middle frontal gyrus; MTG, middle temporal gyrus; MTHFR, 5,10-methylenetetrahydrofolate reductase; NEP, neprilysin; NF-κB, nuclear transcription factor kappa B; PP2A, protein phosphatase 2A; PS, presenilin; S100A2, S100 calcium-binding protein A2; SORBS3, sorbin and v-src avian sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog homology 3 domain containing3; SP1, specificity factor 1; TET1, ten-eleven translocation 1; SK-N-SH, SK-N-BE, human neuroblastoma cell lines; N2A, neuro-2a cell line; CEC, circulating endothelial cells; N.S., not specified; BS, bisulfite sequencing; HPLC: high-performance liquid chromatography; IHC, immunohistochemistry; MS-PCR: methylation specific-PCR.