Epigenetic mechanisms might be involved in Alzheimer’s disease (AD). Genetic polymorphisms in several genes, including APOE (Apolipoprotein E), PSEN1 (Presenilin 1), CR1 (Complement receptor 1), and PICALM (Phosphatidylinositol binding clathrin assembly protein), have been associated to an increased AD risk. However, data regarding methylation of these specific genes are lacking. We evaluated DNA methylation measured by quantitative bisulfite-PCR pyrosequencing in 43 AD patients and 38 healthy subjects (HS). In a multivariate age- and gender-adjusted model, PICALM methylation was decreased in AD compared to HS (mean = 3.54 and 4.63, respectively, p = 0.007). In AD, PICALM methylation level was also positively associated to Mini-Mental Scale Examination (MMSE) score (percent change 3.48%, p = 0.008). Moreover, a negative association between PICALM methylation and age was observed only in HS (percent change – 2.29%, p = 0.002). In conclusion, our data suggest a possible role of PICALM methylation in AD, particularly related to cognitive function. Given the small study sample and the associative nature of our study, further prospective investigations are required to assess the dynamics of DNA methylation in the early stages of AD development.
ScheltensP, BlennowK, BretelerMM, de StrooperB, FrisoniGB, SallowayS, Van der FlierWM (2016) Alzheimer’s disease. Lancet388, 505–517.
2.
BallMJ (1977) Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia. A quantitative study. Acta Neuropathol37, 111–118.
3.
ThomannPA, KaiserE, SchonknechtP, PantelJ, EssigM, SchroderJ (2009) Association of total tau and phosphorylated tau 181 protein levels in cerebrospinal fluid with cerebral atrophy in mild cognitive impairment and Alzheimer disease. J Psychiatry Neurosci34, 136–142.
4.
SchonknechtP, PantelJ, HartmannT, WerleE, VolkmannM, EssigM, AmannM, ZanabiliN, BardenheuerH, HuntA, SchroderJ (2003) Cerebrospinal fluid tau levels in Alzheimer’s disease are elevated when compared with vascular dementia but do not correlate with measures of cerebral atrophy. Psychiatry Res120, 231–238.
HardyJ, SelkoeDJ (2002) The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science297, 353–356.
7.
HarveyRJ, Skelton-RobinsonM, RossorMN (2003) The prevalence and causes of dementia in people under the age of 65 years. J Neurol Neurosurg Psychiatry74, 1206–1209.
KulisM, QueirosAC, BeekmanR, Martin-SuberoJI (2013) Intragenic DNA methylation in transcriptional regulation, normal differentiation and cancer. Biochim Biophys Acta1829, 1161–1174.
17.
RosesAD (1996) Apolipoprotein E in neurology. Curr Opin Neurol9, 265–270.
18.
WolfeMS, XiaW, OstaszewskiBL, DiehlTS, KimberlyWT, SelkoeDJ (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature398, 513–517.
MorganBP (1999) Regulation of the complement membrane attack pathway. Crit Rev Immunol19, 173–198.
22.
DreylingMH, Martinez-ClimentJA, ZhengM, MaoJ, RowleyJD, BohlanderSK (1996) The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10 gene and CALM, encoding a new member of the AP-3 clathrin assembly protein family. Proc Natl Acad Sci U S A93, 4804–4809.
23.
TebarF, BohlanderSK, SorkinA (1999) Clathrin assembly lymphoid myeloid leukemia (CALM) protein: Localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic. Mol Biol Cell10, 2687–2702.
24.
KanatsuK, HoriY, TakatoriS, WatanabeT, IwatsuboT, TomitaT (2016) Partial loss of CALM function reduces Abeta42 production and amyloid deposition in vivo. Hum Mol Genet25, 3988–3997.
25.
QaziTJ, QuanZ, MirA, QingH (2018) Epigenetics in Alzheimer’s disease: Perspective of DNA methylation. Mol Neurobiol55, 1026–1044.
26.
ForakerJ, MillardSP, LeongL, ThomsonZ, ChenS, KeeneCD, BekrisLM, YuCE (2015) The APOE gene is differentially methylated in Alzheimer’s disease. J Alzheimers Dis48, 745–755.
27.
TannorellaP, StoccoroA, TognoniG, PetrozziL, SalluzzoMG, RagalmutoA, SicilianoG, HaslbergerA, BoscoP, BonuccelliU, MiglioreL, CoppedeF (2015) Methylation analysis of multiple genes in blood DNA of Alzheimer’s disease and healthy individuals. Neurosci Lett600, 143–147.
28.
DiFrancesco A, ArosioB, FalconiA, Micioni Di BonaventuraMV, KarimiM, MariD, CasatiM, MaccarroneM, D’AddarioC (2015) Global changes in DNA methylation in Alzheimer’s disease peripheral blood mononuclear cells. Brain Behav Immun45, 139–144.
29.
CropleyJE, MartinDI, SuterCM (2008) Germline epimutation in humans. Pharmacogenomics9, 1861–1868.
30.
MirmohammadsadeghA, MariniA, NambiarS, HassanM, TannapfelA, RuzickaT, HenggeUR (2006) Epigenetic silencing of the PTEN gene in melanoma. Cancer Res66, 6546–6552.
31.
BollatiV, GalimbertiD, PergoliL, DallaValle E, BarrettaF, CortiniF, ScarpiniE, BertazziPA, BaccarelliA (2011) DNA methylation in repetitive elements and Alzheimer disease. Brain Behav Immun25, 1078–1083.
32.
McKhannG, DrachmanD, FolsteinM, KatzmanR, PriceD, StadlanEM (1984) Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology34, 939–944.
33.
DuboisB, FeldmanHH, JacovaC, DekoskyST, Barberger-GateauP, CummingsJ, DelacourteA, GalaskoD, GauthierS, JichaG, MeguroK, O’BrienJ, PasquierF, RobertP, RossorM, SallowayS, SternY, VisserPJ, ScheltensP (2007) Research criteria for the diagnosis of Alzheimer’s disease: Revising the NINCDS-ADRDA criteria. Lancet Neurol6, 734–746.
34.
StraussE, ShermanEMS, SpreenO (2006) A compendium of neuropsychological tests: Administration, norms, and commentary, Oxford University Press, Oxford; New York.
35.
CreavinST, WisniewskiS, Noel-StorrAH, TrevelyanCM, HamptonT, RaymentD, ThomVM, NashKJ, ElhamouiH, MilliganR, PatelAS, TsivosDV, WingT, PhillipsE, KellmanSM, ShackletonHL, SingletonGF, NealeBE, WattonME, CullumS (2016) Mini-Mental State Examination (MMSE) for the detection of dementia in clinically unevaluated people aged 65 and over in community and primary care populations, Cochrane Database Syst Rev, CD011145.
36.
SellebjergF, JensenCV, ChristiansenM (2000) Intrathecal IgG synthesis and autoantibody-secreting cells in multiple sclerosis. J Neuroimmunol108, 207–215.
37.
AndreasenN, BlennowK (2005) CSF biomarkers for mild cognitive impairment and early Alzheimer’s disease. Clin Neurol Neurosurg107, 165–173.
38.
YangAS, EstecioMR, DoshiK, KondoY, TajaraEH, IssaJP (2004) A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements, Nucleic Acids Res32, e38.
39.
BollatiV, BaccarelliA, HouL, BonziniM, FustinoniS, CavalloD, ByunHM, JiangJ, MarinelliB, PesatoriAC, BertazziPA, YangAS (2007) Changes in DNA methylation patterns in subjects exposed to low-dose benzene. Cancer Res67, 876–880.
40.
ChouliarasL, RuttenBP, KenisG, PeerboomsO, VisserPJ, VerheyF, van OsJ, SteinbuschHW, van den HoveDL (2010) Epigenetic regulation in the pathophysiology of Alzheimer’s disease. Prog Neurobiol90, 498–510.
41.
WahlS, DrongA, LehneB, LohM, ScottWR, KunzeS, TsaiPC, RiedJS, ZhangW, YangY, TanS, FioritoG, FrankeL, GuarreraS, KaselaS, KriebelJ, RichmondRC, AdamoM, AfzalU, Ala-KorpelaM, AlbettiB, AmmerpohlO, ApperleyJF, Beekman M, BertazziPA, BlackSL, BlancherC, BonderMJ, BroschM, Carstensen-KirbergM, de CraenAJ, de LusignanS, DehghanA, ElkalaawyM, FischerK, FrancoOH, GauntTR, HampeJ, HashemiM, IsaacsA, JenkinsonA, JhaS, KatoN, KroghV, LaffanM, MeisingerC, MeitingerT, MokZY, MottaV, NgHK, NikolakopoulouZ, NteliopoulosG, PanicoS, PervjakovaN, ProkischH, RathmannW, RodenM, RotaF, RozarioMA, SandlingJK, SchafmayerC, SchrammK, SiebertR, SlagboomPE, SoininenP, StolkL, StrauchK, TaiES, TarantiniL, ThorandB, TigchelaarEF, TuminoR, UitterlindenAG, van DuijnC, van MeursJB, VineisP, WickremasingheAR, WijmengaC, YangTP, YuanW, ZhernakovaA, BatterhamRL, SmithGD, DeloukasP, HeijmansBT, HerderC, HofmanA, LindgrenCM, MilaniL, van der HarstP, PetersA, IlligT, ReltonCL, WaldenbergerM, JarvelinMR, BollatiV, SoongR, SpectorTD, ScottJ, McCarthyMI, ElliottP, BellJT, MatulloG, GiegerC, KoonerJS, GrallertH, ChambersJC (2017) Epigenome-wideassociation study of body mass index, and the adverse outcomes ofadiposity. Nature541, 81–86.
42.
JamesSJ, PogribnyIP, PogribnaM, MillerBJ, JerniganS, MelnykS (2003) Mechanisms of DNA damage, DNA hypomethylation, and tumor progression in the folate/methyl-deficient rat model of hepatocarcinogenesis. J Nutr133, 3740S–3747S.
43.
HernandezHG, MahechaMF, MejiaA, ArboledaH, ForeroDA (2014) Global long interspersed nuclear element 1 DNA methylation in a Colombian sample of patients with late-onset Alzheimer’s disease. Am J Alzheimers Dis Other Demen29, 50–53.
44.
KautO, RamirezA, PieperH, SchmittI, JessenF, WullnerU (2014) DNA methylation of the TNF-alpha promoter region in peripheral blood monocytes and the cortex of human Alzheimer’s disease patients. Dement Geriatr Cogn Disord38, 10–15.
45.
HarelA, WuF, MattsonMP, MorrisCM, YaoPJ (2008) Evidence for CALM in directing VAMP2 trafficking. Traffic9, 417–429.
46.
XiaoQ, GilSC, YanP, WangY, HanS, GonzalesE, PerezR, CirritoJR, LeeJM (2012) Role of phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) in intracellular amyloid precursor protein (APP) processing and amyloid plaque pathogenesis. J Biol Chem287, 21279–21289.
47.
ScarpaS, CavallaroRA, D’AnselmiF, FusoA (2006) Gene silencing through methylation: An epigenetic intervention on Alzheimer disease. J Alzheimers Dis9, 407–414.
