Skip to main content

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

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.

This is a preview of subscription content, access via your institution.

Fig. 1

Abbreviations

Aβ:

Amyloid beta

APP:

Amyloid precursor protein

DNAm:

DNA methylation

DS:

Down syndrome

Hcy:

Homocysteine

SAH:

S-adenosylhomocysteine

SAM:

S-adenosylmethionine

References

  • 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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Alisch, R. S., et al. (2012). Age-associated DNA methylation in pediatric populations. Genome Research, 22, 623–632.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Bacalini, M. G., et al. (2015). Identification of a DNA methylation signature in blood cells from persons with Down Syndrome. Aging, 7, 82–96.

    Article  PubMed  Google Scholar 

  • 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.

    CAS  Article  PubMed  Google Scholar 

  • Endo, K., et al. (2015). Establishment of the MethyLight assay for assessing aging, cigarette smoking, and alcohol consumption. BioMed Research International, 2015, 451981.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fusco, F. R., & Giampa, C. (2015). Phosphodiesterases as therapeutic targets for Huntington’s disease. Current Pharmaceutical Design, 21, 365–377.

    CAS  Article  PubMed  Google Scholar 

  • 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.

    CAS  Article  Google Scholar 

  • Garinis, G. A., et al. (2008). DNA damage and ageing: new-age ideas for an age-old problem. Nature Cell Biology, 10, 1241–1247.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Ge, Y., et al. (2008). The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy. Leukemia, 22, 521–529.

    CAS  Article  PubMed  Google Scholar 

  • 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.

    CAS  Article  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Horvath, S., et al. (2015). Accelerated epigenetic aging in Down syndrome. Aging Cell, 14, 491–495.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  Article  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Mann, D. M. (1988). The pathological association between Down syndrome and Alzheimer disease. Mechanisms of Ageing and Development, 43, 99–136.

    CAS  Article  PubMed  Google Scholar 

  • 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.

    CAS  Article  PubMed  Google Scholar 

  • 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.

    CAS  Article  Google Scholar 

  • 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.

    CAS  Article  PubMed  Google Scholar 

  • Pogribna, M., et al. (2001). Homocysteine metabolism in children with Down syndrome: in vitro modulation. American Journal of Human Genetics, 69, 88–95.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Roizen, N. J., & Patterson, D. (2003). Down’s syndrome. Lancet, 361, 1281–1289.

    Article  PubMed  Google Scholar 

  • Sailani, M. R., et al. (2015). DNA-methylation patterns in trisomy 21 using cells from monozygotic twins. PLoS ONE, 10, e0135555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  Article  PubMed  Google Scholar 

  • 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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Weidner, C. I., & Wagner, W. (2014). The epigenetic tracks of aging. Biological Chemistry, 395, 1307–1314.

    CAS  Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We acknowledge the engagements of Kathrin Hartmuth and Nicole Klein in patient’s recruitments.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rima Obeid.

Ethics declarations

Conflict of interest

The authors confirm that there is no conflict of interest regarding the content for this manuscript.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 21 kb)

Supplementary material 2 (PPTX 69 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Obeid, R., Hübner, U., Bodis, M. et al. Plasma Amyloid Beta 1-42 and DNA Methylation Pattern Predict Accelerated Aging in Young Subjects with Down Syndrome. Neuromol Med 18, 593–601 (2016). https://doi.org/10.1007/s12017-016-8413-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12017-016-8413-y

Keywords

  • Trisomy 21
  • Amyloid beta
  • DNA methylation
  • Aging
  • Epigenomics