阿尔茨海默病患者脑内β淀粉样蛋白斑块的显微拉曼光谱定量化学成像
Quantitative chemical imaging of amyloid-β plaques with Raman micro-spectroscopy in human Alzheimer's diseased brains
摘要：
阿尔茨海默病（AD）是一种神经退行性疾病，是老年人痴呆的最常见原因。老年斑中淀粉样蛋白- $β$（A $β$）的细胞外积累是发病机制中的主要事件，并且有越来越多的证据表明脂质途径的失调与疾病有关，然而这两者之间的联系仍在研究中。在这项工作中，我们研究了人脑样本，从11个AD患者和对照组年龄匹配的受试者没有AD，使用无标记的化学特定的拉曼显微光谱。使用有效的定量无监督/部分监督非负矩阵分解方法对收集的图像数据进行定量分析，以检索样品化学成分的浓度图和光谱。与对照组相比，在AD组织中观察到脂质组成的显著变化以及氧化应激生物标志物浓度的增加。特别是，分析显示胆固醇酯与饱和长链脂肪酸（FA）、A $β$原纤维、花生酸、纤维蛋白、胶原样淀粉样蛋白生成组分（CLAC）、$β$ -胡萝卜素和磁铁矿的累积，共定位于AD人脑的A $β$斑块中，并在原纤维核心处显示出最高浓度，在边缘处显示出最低浓度。这一发现为新的抗炎和抗氧化药物策略开辟了前景，旨在恢复脑内稳态作为AD的潜在治疗方法。我们还表明，通过空间浓度直方图的手段，这些识别出的物种从非痴呆对照大脑AD分离，有利于AD诊断。
英文摘要：
Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia in the elderly. The extracellular accumulation of amyloid-$β$ (A$β$) in senile plaques is a principal event in the pathogenesis and there is growing evidence that the dysregulation of lipid pathways is implicated in the disease, however the link between these two is still under study. In this work, we investigated human brain samples, from 11 AD patients and a control cohort of age-matched subjects without AD, using label-free chemically-specific Raman micro-spectroscopy. The collected image data were quantitatively analysed using an efficient quantitative unsupervised/partially supervised non-negative matrix factorization method, to retrieve the concentration maps and spectra of the samples' chemical constituents. Significant changes in lipid composition as well as increased concentrations of oxidative stress bio-markers were observed in AD tissues compared to the control. In particular, the analysis revealed accumulations of cholesteryl esters with saturated long-chain fatty acids (FAs), A$β$ fibrils, arachidic acid, fibrin, collagen-like amyloidogenic component (CLAC), $β$-carotene and magnetite, co-localising in A$β$ plaques of AD human brains and exhibiting concentrations highest at the fibrillar core and lowest at the rim. This finding opens perspectives for new anti-inflammatory and antioxidant drug strategies, designed to restore brain homeostasis as potential therapeutics of AD. We also demonstrate by the means of spatial concentration histograms that these identified species separate AD from non-demented control brains, beneficial for AD diagnosis.
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