Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
J Alzheimers Dis. 2011;27(4):819-33. doi: 10.3233/JAD-2011-111013.
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.
迟发性阿尔茨海默病（LOAD）的发病初期仍不清楚；然而，神经退行性变的渐进性和潜伏性表明，触发事件发生在生命早期。在婴儿期接触铅（Pb）的衰老灵长类动物表现出淀粉样β蛋白前体（AβPP）、淀粉样β（Aβ）的过度表达和增强的病理性神经退行性变。在这项研究中，我们测量了广泛的大脑特异性基因的潜伏表达，并探索了表观遗传途径是否介导了这种潜伏的分子和病理变化。我们分析了与 DNA 甲基化相关的蛋白质的水平，即 DNA 甲基转移酶 1（Dnmt1）、DNA 甲基转移酶 3a（Dnmt3a）、甲基-CpG 结合蛋白-2（MeCP2）和参与组蛋白修饰（乙酰化和甲基化组蛋白）的蛋白质。我们监测了这些中间产物在整个生命过程中的表达谱，并分析了它们在 23 岁时暴露于 Pb 的灵长类动物大脑中的水平。发育性 Pb 暴露改变了阵列基因的基因表达，这些基因主要受到抑制，而上调基因较少。基因的潜伏诱导和抑制伴随着 Dnmts、MeCP2 和参与组蛋白修饰的蛋白质水平显著降低。DNA 甲基转移酶的衰减与去甲基化作用一致，促进基因的上调，而组蛋白修饰剂的改变与基因的抑制有关。因此，我们推断早期生活中接触 Pb 可以重新编程基因表达，导致基因的上调和下调，通过交替的表观遗传途径促进老年神经退行性变的增强。
