Probing the origin and evolution of low-oxidation state iron and copper nanoparticles in the brain

阿尔茨海默氏症和帕金森氏症等神经退行性疾病的特征是自然产生的蛋白质水平异常，这些蛋白质聚集在一起，在大脑中形成致密的沉积。在阿尔茨海默氏症中，这些沉积物是由淀粉样β蛋白形成的，通常被称为淀粉样斑块。这些斑块如何影响疾病的发生和发展仍不完全清楚。然而，对淀粉样斑块的详细研究表明，它们普遍含有不同金属的微观颗粒(称为纳米颗粒)。在大脑中发现金属并不令人惊讶，因为人体在日常功能中需要令人难以置信的至少10种不同的金属元素，我们的大部分铁以微小的氧化铁纳米颗粒(一种铁锈)的形式存在。更令人惊讶的是，我们在淀粉样斑块中观察到的铁和铜纳米颗粒，并不是典型的氧化金属，如铁锈。相反，使用复杂的X射线显微镜方法，我们发现这些粒子实际上稳定在所谓的低氧化态，包括纯金属元素形式。这一发现类似于在田野中放置多年后发现了一颗闪闪发光的金属铁钉。就像我们预计指甲会因为金属表面的化学反应而随着时间的推移而氧化一样，纳米颗粒(相对于它们的大小具有更大的表面积)更有可能被氧化。当这种纳米颗粒暴露在活组织中时，这种表面反应性也会导致毒性。因此，了解处于这种低氧化状态的纳米颗粒是如何稳定在大脑中发现的蛋白质沉积中的，可以为了解大脑中金属和蛋白质之间的相互作用以及这如何导致衰老和疾病提供至关重要的见解。可能是金属氧化物纳米颗粒本身驱动了蛋白质的异常沉积，并在此过程中转化为低氧化态。寻找这些金属-蛋白质相互作用发生在脑组织中的证据，以及研究转化可能进行的机制，是该项目的关键目标之一。然而，同样重要的是找到被蛋白质转化的氧化金属颗粒的来源。蛋白质和大脑中已经存在的金属氧化物的生物来源之间可能发生相互作用，但也可能涉及来自身体以外的来源。现在有大量证据表明，存在于某些空气污染形式中的超细金属氧化物颗粒可以进入大脑。他们似乎是通过绕过大脑的自然防御来实现这一点的，而自然防御通常会阻止异物进入。因此，该项目的另一个目标是调查从英国已知污染地点收集的环境纳米颗粒，并评估这些颗粒在大脑中转化为低氧化状态的可能性。该项目将使用最先进的新方法与物理科学方法相结合，建立关于将金属和蛋白质与人类大脑的衰老和疾病联系起来的生化过程的基本新知识。这在开发治疗阿尔茨海默氏症等疾病的新药方面将特别重要，目前这些新药只专注于蛋白质沉积，并取得了一定程度的成功。同时也针对金属的联合策略将为有效的治疗带来新的希望，而了解氧化铁是如何转化的可能有助于开发更敏感的MRI诊断。后者可以利用蛋白质聚集过程中金属形式铁的积累来检测大脑萎缩之前大脑中的关键变化。最终，这可能会对早期干预产生巨大影响，治疗方法是针对特定金属形态量身定做的。

Neurodegenerative diseases such as Alzheimer's and Parkinson's are characterised by abnormal levels of naturally occurring proteins that clump together to form dense deposits in the brain. In Alzheimer's these deposits are formed from the amyloid-beta protein, and often termed amyloid plaques. The ways in which these plaques influence the onset and progression of the disease are still not fully understood. However, detailed studies of amyloid plaques have revealed a prevalence for them to contain microscopic particles (called nanoparticles) of different metals. It is not surprising to find metals in the brain, as the human body needs an incredible range of at least 10 different metallic elements in its everyday function, with much of our iron present as tiny nanoparticles of iron oxide (a form of rust). What is far more surprising is that the iron and copper nanoparticles we have observed within amyloid plaques, are not typical of oxidized metals such as rust. Instead, using sophisticated x-ray microscopy methods, we found that these particles were in fact stabilized in what are called low-oxidation states, including pure metallic elemental forms. This discovery is akin to finding a shiny metallic iron nail after it has been left in a field for many years. Just as we would expect the nail to oxidize over time due to the chemical reactivity of the metal surface, the nanoparticles (which have a much higher surface area relative to their size) are even more likely to oxidize. This surface reactivity can also result in toxicity when such nanoparticles are exposed to living tissue. Therefore, understanding how nanoparticles in this low-oxidation state are stabilized within the protein deposits found in the brain, could provide crucial insight into the interplay between metals and proteins in the brain and how this contributes to aging and disease. It is possible that the metal oxide nanoparticles themselves could drive the abnormal protein deposition, and in the process be transformed to low-oxidation states. Looking for evidence that these metal-protein interactions occur in brain tissue, as well as investigating the mechanisms by which the transformations could proceed, is one of the key aims of this project. Equally important though is finding the source of the oxidised metal particles that are transformed by the proteins. Interactions could occur between proteins and biological sources of metal oxides already present in the brain, but it is also possible that sources from outside the body are involved. Substantial evidence now exists suggesting ultrafine metal oxide particles that are present in some airborne forms of pollution, can enter the brain. It seems they do this via routes that bypass the brain's natural defences that normally prevent foreign material entering. A further aim of this project is therefore to investigate environmental nanoparticles collected from sites of known pollution in the UK, and to assess the likelihood that such particles are transformed to low-oxidation states in the brain. The project will use new state-of-the-art methods combined with physical science approaches, to build fundamental new knowledge regarding the biochemical processes that connect metals and proteins with aging and disease in the human brain. This will be of particular importance in the development of new drugs to treat diseases such as Alzheimer's, which currently focus only on the protein deposits with modest levels of success. Combined strategies that also target metals will offer new hope for effective treatments, whilst knowledge of how iron oxides are transformed could help develop more sensitive MRI diagnosis. The latter could use the accumulation of metallic forms of iron during protein aggregation to detect key changes in the brain prior to brain atrophy. Ultimately this could have huge impact on early interventions, with treatments tailored to target specific metal forms.