Infant exposure to lead (Pb) and epigenetic modifications in the aging primate brain: Implications for Alzheimer's disease

Syed Waseem Bihaqi, Hui Huang, Jinfang Wu, Nasser H. Zawia*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

135 Citations (Scopus)

Abstract

The beginnings of late onset Alzheimer's disease (LOAD) are still unknown; however, the progressive and latent nature of neurodegeneration suggests that the triggering event occurs earlier in life. Aging primates exposed to lead (Pb) as infants exhibited an overexpression of the amyloid-β protein precursor (AβPP), amyloid-β (Aβ) and enhanced pathologic neurodegeneration. In this study, we measured the latent expression of a wide array of brain-specific genes and explored whether epigenetic pathways mediated such latent molecular and pathological changes. We analyzed the levels of proteins associated with DNA methylation, i.e., DNA methyltransferase 1 (Dnmt1), DNA methyltransferase3a (Dnmt3a), methyl-CpG binding protein-2 (MeCP2) and those involved in histone modifications (acetylated and methylated histones). We monitored the expression profiles of these intermediates across the lifespan and analyzed their levels in 23-year-old primate brains exposed to Pb as infants. Developmental Pb exposure altered the gene expression of the arrayed genes, which were predominately repressed, with fewer upregulated genes. The latent induction and repression of genes was accompanied by a significant decrease in the protein levels of Dnmts, MeCP2, and proteins involved in histone modifications. The attenuation of DNA methylation enzymes is consistent with hypomethylating effects, which promote upregulation of the genes, while the alterations in the histone modifiers are associated with the repression of genes. Hence, we deduce that early life exposure to Pb can reprogram gene expression resulting in both upregulation and down-regulation of genes through alternate epigenetic pathways contributing to an enhancement in neurodegeneration in old age.

Original languageEnglish
Pages (from-to)819-833
Number of pages15
JournalJournal of Alzheimer's Disease
Volume27
Issue number4
DOIs
Publication statusPublished - 2011
Externally publishedYes

Keywords

  • Alzheimer's disease
  • DNA methylation
  • Pb
  • aging
  • gene expression
  • histone modifications

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