NeuroMolecular Medicine

, Volume 18, Issue 4, pp 593–601 | Cite as

Plasma Amyloid Beta 1-42 and DNA Methylation Pattern Predict Accelerated Aging in Young Subjects with Down Syndrome

  • Rima Obeid
  • Ulrich Hübner
  • Marion Bodis
  • Juergen Geisel
Original Paper

Abstract

Gene methylation is an age-related dynamic process that influences diseases. Premature aging and disturbed methylation are components of Down syndrome (DS). We studied blood biomarkers and DNA methylation (DNAm) of three CpG sites (ASPA, ITGA2B, and PDE4C) in 60 elderly subjects (mean age = 68 years), 31 subjects with DS (12.1 years) and 44 controls (12.8 years). Plasma concentrations of amyloid beta (Aβ) 1-42 and biomarkers of methylation were measured in the young groups. Subjects with DS had significantly higher concentrations of plasma S-adenosylhomocysteine (SAH) and Aβ and reduced S-adenosylmethionine/SAH ratio compared with the controls. Methylations (%) of ASPA and ITGA2B were lower in DS [mean difference; 95 % confidence intervals = −2.2 (−4.5, 0.1) for ASPA and −5.0 (−8.9, −1.1) for ITGA2B]. Methylation of PDE4C did not differ between the groups. The sum of z-scores for methylations of ASPA and ITGA2B, both of which declined with age, was significantly lower in DS [−1.01 (−1.93, −0.20), p = 0.017]. Subjects with DS were found to be 3.1 (1.5–4.6) years older than their predicted age based on a regression model of the controls. Elevated SAH levels predicted lower DNAm of ASPA and ITGA2B in stepwise regression analysis. Therefore, methylation of three CpGs combined with plasma Aβ has shown a 3-year accelerated aging in subjects with DS at the age of 12 years. Disorders in the methylation cycle explained pathoepigenetic modifications in subjects with DS. The influence of modifications in the methylation cycle on epigenetic markers of aging warrants further investigations.

Keywords

Trisomy 21 Amyloid beta DNA methylation Aging Epigenomics 

Abbreviations

Amyloid beta

APP

Amyloid precursor protein

DNAm

DNA methylation

DS

Down syndrome

Hcy

Homocysteine

SAH

S-adenosylhomocysteine

SAM

S-adenosylmethionine

Supplementary material

12017_2016_8413_MOESM1_ESM.docx (21 kb)
Supplementary material 1 (DOCX 21 kb)
12017_2016_8413_MOESM2_ESM.pptx (70 kb)
Supplementary material 2 (PPTX 69 kb)

References

  1. Aimi, J., et al. (1990). De novo purine nucleotide biosynthesis: cloning of human and avian cDNAs encoding the trifunctional glycinamide ribonucleotide synthetase-aminoimidazole ribonucleotide synthetase-glycinamide ribonucleotide transformylase by functional complementation in E. coli. Nucleic Acids Research, 18, 6665–6672.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Alisch, R. S., et al. (2012). Age-associated DNA methylation in pediatric populations. Genome Research, 22, 623–632.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bacalini, M. G., et al. (2015). Identification of a DNA methylation signature in blood cells from persons with Down Syndrome. Aging, 7, 82–96.CrossRefPubMedGoogle Scholar
  4. Bollati, V., et al. (2009). Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mechanisms of Ageing and Development, 130, 234–239.CrossRefPubMedGoogle Scholar
  5. Endo, K., et al. (2015). Establishment of the MethyLight assay for assessing aging, cigarette smoking, and alcohol consumption. BioMed Research International, 2015, 451981.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Fusco, F. R., & Giampa, C. (2015). Phosphodiesterases as therapeutic targets for Huntington’s disease. Current Pharmaceutical Design, 21, 365–377.CrossRefPubMedGoogle Scholar
  7. Fuso, A., et al. (2012). S-adenosylmethionine reduces the progress of the Alzheimer-like features induced by B-vitamin deficiency in mice. Neurobiology of Aging, 33, 1482.e1–1482.e16.CrossRefGoogle Scholar
  8. Garinis, G. A., et al. (2008). DNA damage and ageing: new-age ideas for an age-old problem. Nature Cell Biology, 10, 1241–1247.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Ge, Y., et al. (2008). The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy. Leukemia, 22, 521–529.CrossRefPubMedGoogle Scholar
  10. Glenner, G. G., & Wong, C. W. (1984). Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochemical and Biophysical Research Communications, 122, 1131–1135.CrossRefPubMedGoogle Scholar
  11. Head, E., et al. (2011). Plasma amyloid-beta as a function of age, level of intellectual disability, and presence of dementia in Down syndrome. Journal of Alzheimer’s Disease, 23, 399–409.PubMedPubMedCentralGoogle Scholar
  12. Horvath, S., et al. (2015). Accelerated epigenetic aging in Down syndrome. Aging Cell, 14, 491–495.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Hübner, U., et al. (2013). Effect of 1 year B and D vitamin supplementation on LINE-1 repetitive element methylation in older subjects. Clinical Chemistry and Laboratory Medicine, 51, 649–655.CrossRefPubMedGoogle Scholar
  14. Jenkins, E. C., et al. (2006). Telomere shortening in T lymphocytes of older individuals with Down syndrome and dementia. Neurobiology of Aging, 27, 941–945.CrossRefPubMedGoogle Scholar
  15. Kane, M. F., et al. (1997). Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Research, 57, 808–811.PubMedGoogle Scholar
  16. Mann, D. M. (1988). The pathological association between Down syndrome and Alzheimer disease. Mechanisms of Ageing and Development, 43, 99–136.CrossRefPubMedGoogle Scholar
  17. Nones, K., et al. (2014). Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling. International Journal of Cancer, 135, 1110–1118.CrossRefPubMedGoogle Scholar
  18. Obeid, R., et al. (2012). Blood biomarkers of methylation in Down syndrome and metabolic simulations using a mathematical model. Molecular Nutrition & Food Research, 56, 1582–1589.CrossRefGoogle Scholar
  19. Obermann-Borst, S. A., et al. (2011). Congenital heart defects and biomarkers of methylation in children: a case-control study. European Journal of Clinical Investigation, 41, 143–150.CrossRefPubMedGoogle Scholar
  20. Pogribna, M., et al. (2001). Homocysteine metabolism in children with Down syndrome: in vitro modulation. American Journal of Human Genetics, 69, 88–95.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Roizen, N. J., & Patterson, D. (2003). Down’s syndrome. Lancet, 361, 1281–1289.CrossRefPubMedGoogle Scholar
  22. Sailani, M. R., et al. (2015). DNA-methylation patterns in trisomy 21 using cells from monozygotic twins. PLoS ONE, 10, e0135555.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Smigielska-Kuzia, J., et al. (2010). Amino acid metabolic processes in the temporal lobes assessed by proton magnetic resonance spectroscopy (1H MRS) in children with Down syndrome. Pharmacological Reports, 62, 1070–1077.CrossRefPubMedGoogle Scholar
  24. Walecki, J., et al. (2011). N-acetylaspartate, choline, myoinositol, glutamine and glutamate (glx) concentration changes in proton MR spectroscopy (1H MRS) in patients with mild cognitive impairment (MCI). Medical Science Monitor, 17, MT105–MT111.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Weidner, C. I., & Wagner, W. (2014). The epigenetic tracks of aging. Biological Chemistry, 395, 1307–1314.CrossRefPubMedGoogle Scholar
  26. Weidner, C. I., et al. (2014). Aging of blood can be tracked by DNA methylation changes at just three CpG sites. Genome Biology, 15, R24.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Rima Obeid
    • 1
    • 2
  • Ulrich Hübner
    • 1
  • Marion Bodis
    • 1
  • Juergen Geisel
    • 1
  1. 1.Department of Clinical Chemistry and Laboratory MedicineSaarland University HospitalHomburg/SaarGermany
  2. 2.Aarhus Institute of Advanced StudiesUniversity of AarhusAarhus CDenmark

Personalised recommendations