已知铝(Al)会引起神经毒性作用,可能导致阿尔茨海默病(AD)的发病机制。最近的研究表明,表观遗传修饰可能有助于铝的神经毒性,尽管机制仍有争议。因此,本研究的目的是总结关于表观遗传机制参与铝诱导的神经毒性的现有数据,尤其是AD型病理。现有数据表明,铝暴露诱导DNA甲基化的破坏,组蛋白修饰,和大脑中的非编码RNA表达。Al暴露后DNA甲基化的改变被证明是由DNA甲基转移酶(DNMT)和十11易位蛋白(TET)的表达和活性变化介导的。Al暴露通过上调组蛋白脱乙酰酶(HDAC)的表达和损害组蛋白甲基化来减少组蛋白乙酰化,最终导致脑源性神经营养因子(BDNF)表达下调和核因子κB(NF-κB)信号的激活。铝暴露的神经毒性作用也与非编码RNA的异常表达有关,特别是microRNA(miR)。Al诱导的miR表达模式通过上调Aβ前体蛋白(APP)和β分泌酶(BACE1)表达来增加淀粉样β(Aβ)的产生而参与AD型病理的发展(miR-29a/b的下调,miR-101、miR-124和Let-7c表达),通过NF-κB信号传导增加神经炎症(miR-9,miR-125b的上调,miR-128和146a),以及调节其他信号通路。此外,减少全球DNA甲基化,改变的组蛋白修饰,和异常miRNA表达与Al暴露受试者的认知能力下降有关。然而,需要进一步的研究来评估表观遗传机制对Al诱导的神经毒性和/或AD发展的贡献.
Aluminum (Al) is known to induce neurotoxic effects, potentially contributing to Alzheimer\'s disease (AD) pathogenesis. Recent studies suggest that epigenetic modification may contribute to Al neurotoxicity, although the mechanisms are still debatable. Therefore, the objective of the present study was to summarize existing data on the involvement of epigenetic mechanisms in Al-induced neurotoxicity, especially AD-type pathology. Existing data demonstrate that Al exposure induces disruption in DNA methylation,
histone modifications, and non-coding RNA expression in brains. Alterations in DNA methylation following Al exposure were shown to be mediated by changes in expression and activity of DNA methyltransferases (DNMTs) and ten-eleven translocation proteins (TETs). Al exposure was shown to reduce
histone acetylation by up-regulating expression of
histone deacetylases (HDACs) and impair
histone methylation, ultimately contributing to down-regulation of brain-derived neurotrophic factor (BDNF) expression and activation of nuclear factor κB (NF-κB) signaling. Neurotoxic effects of Al exposure were also associated with aberrant expression of non-coding RNAs, especially microRNAs (miR). Al-induced patterns of miR expression were involved in development of AD-type pathology by increasing amyloid β (Aβ) production through up-regulation of Aβ precursor protein (APP) and β secretase (BACE1) expression (down-regulation of miR-29a/b, miR-101, miR-124, and Let-7c expression), increasing in neuroinflammation through NF-κB signaling (up-regulation of miR-9, miR-125b, miR-128, and 146a), as well as modulating other signaling pathways. Furthermore, reduced global DNA methylation, altered
histone modification, and aberrant miRNA expression were associated with cognitive decline in Al-exposed subjects. However, further studies are required to evaluate the contribution of epigenetic mechanisms to Al-induced neurotoxicity and/or AD development.