Neurula Laboratory, Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Australia; Centre for Stem Cell Ageing and Regenerative Engineering, The University of Queensland, Brisbane, Australia.
Neurula Laboratory, Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
J Mol Biol. 2019 Apr 19;431(9):1843-1868. doi: 10.1016/j.jmb.2019.01.018. Epub 2019 Jan 18.
As the median age of the population increases, the number of individuals with Alzheimer's disease (AD) and the associated socio-economic burden are predicted to worsen. While aging and inherent genetic predisposition play major roles in the onset of AD, lifestyle, physical fitness, medical condition, and social environment have emerged as relevant disease modifiers. These environmental risk factors can play a key role in accelerating or decelerating disease onset and progression. Among known environmental risk factors, chronic exposure to various metals has become more common among the public as the aggressive pace of anthropogenic activities releases excess amount of metals into the environment. As a result, we are exposed not only to essential metals, such as iron, copper, zinc and manganese, but also to toxic metals including lead, aluminum, and cadmium, which perturb metal homeostasis at the cellular and organismal levels. Herein, we review how these metals affect brain physiology and immunity, as well as their roles in the accumulation of toxic AD proteinaceous species (i.e., β-amyloid and tau). We also discuss studies that validate the disruption of immune-related pathways as an important mechanism of toxicity by which metals can contribute to AD. Our goal is to increase the awareness of metals as players in the onset and progression of AD.
随着人口年龄中位数的增长，预计阿尔茨海默病（AD）患者的数量以及由此带来的社会经济负担将会恶化。虽然衰老和内在遗传易感性在 AD 的发病中起主要作用，但生活方式、身体健康、身体状况和社会环境已成为相关的疾病修饰因子。这些环境风险因素在加速或延缓疾病的发生和进展方面起着关键作用。在已知的环境风险因素中，由于人类活动的积极步伐将大量金属释放到环境中，公众慢性接触各种金属的情况变得更加普遍。因此，我们不仅接触到铁、铜、锌和锰等必需金属，还接触到铅、铝和镉等有毒金属，这些金属会在细胞和机体水平上扰乱金属内稳态。在此，我们综述了这些金属如何影响大脑的生理和免疫功能，以及它们在有毒的 AD 蛋白（即β-淀粉样蛋白和 tau）积累中的作用。我们还讨论了一些验证免疫相关途径被破坏是金属导致 AD 的毒性的重要机制的研究。我们的目标是提高对金属在 AD 的发病和进展中所起作用的认识。
