Correlative Microscopy to Localize and Characterize Iron Deposition in Alzheimer's Disease.
Correlative Microscopy to Localize and Characterize Iron Deposition in Alzheimer's Disease.
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DOI：
10.3233/adr-200234
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发表时间：
2020-12-21
期刊：
影响因子：
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通讯作者：
Zeineh MM
中科院分区：
文献类型：
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作者：
Madsen SJ;DiGiacomo PS;Zeng Y;Goubran M;Chen Y;Rutt BK;Born D;Vogel H;Sinclair R;Zeineh MM
最近的证据表明，铁的积累，特别是亚铁的积累，可能通过产生氧化应激在阿尔茨海默病(AD)神经退行性变的发生和发展中发挥作用。为了定位和表征AD中铁的沉积和氧化状态，我们分析了四例晚期AD患者的人类海马区尸检标本，这些标本之前都有相关的MRI组织学特征。我们在更高分辨率的透射电子显微镜上对感兴趣的特定富铁区域的表面和横截面进行扫描电子显微镜(SEM)、能量色散光谱(EDS)和电子能量损失光谱(EELS)。以前分析过的特定区域用扫描电子显微镜显示，并用能谱分析确认为富铁矿床。随后使用聚焦离子束横截面和扫描电子显微镜的分析表征了铁在整个3D体积中的沉积，证实了铁在整个沉积物中的存在，并在四个样品中的两个样品中证明了与锌的共位。对传统组织学切片的分析显示，所分析的沉积与淀粉样蛋白和tau沉积重叠。在用扫描电子显微镜(STEM)对单个铁矿床进行高分辨率分析后，我们证明了单色STEM-EELS在辨别沉积物中铁的相对氧化态方面的潜力。这些发现表明，铁存在于AD的海马体中，并可以使用MRI和EM技术相结合的方法进行可视化和表征。相对氧化状态的改变可能表明铁与阿尔茨海默病的氧化应激之间存在直接联系。因此，这些方法可能会测量一种改变的相对氧化状态，这可能表明铁与阿尔茨海默病患者的氧化应激之间存在直接联系。此外，我们还展示了结合AD病理的常用组织学标记分析金属沉积的能力，为未来深入了解Aβ、tau、铁和其他可能的金属(如锌)之间的分子相互作用铺平了道路。
Recent evidence suggests that the accumulation of iron, specifically ferrous Fe2+, may play a role in the development and progression of neurodegeneration in Alzheimer’s disease (AD) through the production of oxidative stress. To localize and characterize iron deposition and oxidation state in AD, we analyzed human hippocampal autopsy samples from four subjects with advanced AD that have been previously characterized with correlative MRI-histology. We perform scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and electron energy loss spectroscopy (EELS) in the higher resolution transmission electron microscope on the surface and cross-sections of specific iron-rich regions of interest. Specific previously analyzed regions were visualized using SEM and confirmed to be iron-rich deposits using EDS. Subsequent analysis using focused ion beam cross-sectioning and SEM characterized the iron deposition throughout the 3-D volumes, confirming the presence of iron throughout the deposits, and in two out of four specimens demonstrating colocalization with zinc. Analysis of traditional histology slides showed the analyzed deposits overlapped both with amyloid and tau deposition. Following higher resolution analysis of a single iron deposit using scanning transmission electron microscope (STEM), we demonstrated the potential of monochromated STEM-EELS to discern the relative oxidation state of iron within a deposit. These findings suggest that iron is present in the AD hippocampus and can be visualized and characterized using combined MRI and EM techniques. An altered relative oxidation state may suggest a direct link between iron and oxidative stress in AD. These methods thus could potentially measure an altered relative oxidation state that could suggest a direct link between iron and oxidative stress in AD. Furthermore, we have demonstrated the ability to analyze metal deposition alongside commonly used histological markers of AD pathology, paving the way for future insights into the molecular interactions between Aβ, tau, iron, and other putative metals, such as zinc.