The accumulation of amyloid plaques and increased brain redox burdens are neuropathological hallmarks of Alzheimer’s disease. Altered metabolism of essential biometals is another feature of Alzheimer’s, with amyloid plaques representing sites of disturbed metal homeostasis. Despite these observations, metal-targeting disease treatments have not been therapeutically effective to date. A better understanding of amyloid plaque composition and the role of the metals associated with them is critical. To establish this knowledge, the ability to resolve chemical variations at nanometer length scales relevant to biology is essential. Here, we present a methodology for the label-free, nanoscale chemical characterization of amyloid plaques within human Alzheimer’s disease tissue using synchrotron X-ray spectromicroscopy. Our approach exploits a C–H carbon absorption feature, consistent with the presence of lipids, to visualize amyloid plaques selectively against the tissue background, allowing chemical analysis to be performed without the addition of amyloid dyes that alter the native sample chemistry. Using this approach, we show that amyloid plaques contain elevated levels of calcium, carbonates, and iron compared to the surrounding brain tissue. Chemical analysis of iron within plaques revealed the presence of chemically reduced, low-oxidation-state phases, including ferromagnetic metallic iron. The zero-oxidation state of ferromagnetic iron determines its high chemical reactivity and so may contribute to the redox burden in the Alzheimer’s brain and thus drive neurodegeneration. Ferromagnetic metallic iron has no established physiological function in the brain and may represent a target for therapies designed to lower redox burdens in Alzheimer’s disease. Additionally, ferromagnetic metallic iron has magnetic properties that are distinct from the iron oxide forms predominant in tissue, which might be exploitable for the in vivo detection of amyloid pathologies using magnetically sensitive imaging. We anticipate that this label-free X-ray imaging approach will provide further insights into the chemical composition of amyloid plaques, facilitating better understanding of how plaques influence the course of Alzheimer’s disease.

中文翻译：

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人脑组织中淀粉样斑块的无标记原位化学表征

淀粉样斑块的积累和大脑氧化还原负担的增加是阿尔茨海默病的神经病理学标志。必需生物金属代谢的改变是阿尔茨海默病的另一个特征，淀粉样斑块代表金属稳态紊乱的部位。尽管有这些观察结果，金属靶向疾病治疗迄今为止尚未取得治疗效果。更好地了解淀粉样斑块的组成以及与其相关的金属的作用至关重要。为了建立这一知识，解决与生物学相关的纳米长度尺度化学变化的能力至关重要。在这里，我们提出了一种使用同步加速器 X 射线光谱显微镜对人类阿尔茨海默病组织内淀粉样斑块进行无标记、纳米级化学表征的方法。我们的方法利用与脂质存在一致的 C-H 碳吸收特征，选择性地在组织背景下可视化淀粉样斑块，从而无需添加改变天然样品化学成分的淀粉样蛋白染料即可进行化学分析。使用这种方法，我们发现与周围的脑组织相比，淀粉样蛋白斑块中钙、碳酸盐和铁的含量升高。对斑块内铁的化学分析表明存在化学还原的低氧化态相，包括铁磁性金属铁。铁磁铁的零氧化态决定了其高化学反应性，因此可能会增加阿尔茨海默氏症大脑中的氧化还原负担，从而导致神经退行性变。铁磁性金属铁在大脑中没有确定的生理功能，可能是旨在降低阿尔茨海默病氧化还原负担的疗法的目标。此外，铁磁金属铁具有与组织中主要的氧化铁形式不同的磁性，这可用于使用磁敏成像体内检测淀粉样蛋白病理。我们预计这种无标记 X 射线成像方法将进一步了解淀粉样斑块的化学成分，从而有助于更好地了解斑块如何影响阿尔茨海默病的病程。