Delineating Amyloid Plaque Associated Neuronal Sphingolipids in Transgenic Alzheimer's Disease Mice (tgArcSwe) Using MALDI Imaging Mass Spectrometry.
Delineating Amyloid Plaque Associated Neuronal Sphingolipids in Transgenic Alzheimer's Disease Mice (tgArcSwe) Using MALDI Imaging Mass Spectrometry.
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DOI：
10.1021/acschemneuro.6b00391
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发表时间：
2017-02-15
影响因子：
5
通讯作者：
Hanrieder J
中科院分区：
文献类型：
--
作者：
Kaya I;Brinet D;Michno W;Syvänen S;Sehlin D;Zetterberg H;Blennow K;Hanrieder J
阿尔茨海默病 (AD) 的主要病理特征是 β-淀粉样蛋白 (Aβ) 和过度磷酸化的 tau 蛋白逐渐聚集和积累成神经毒性沉积物。 Aβ 聚集被认为是驱动疾病进展的关键早期诱导因素。然而，促进神经毒性 Aβ 聚集的因素仍然难以捉摸。成像质谱（IMS）是一种强大的技术，可以全面阐明生物组织切片中脂质、肽和蛋白质的空间分布模式。在本研究中，基于基质辅助激光解吸/电离 (MALDI) 质谱 (MS) 的成像被用于转基因阿尔茨海默病小鼠 (tgArcSwe) 脑组织，以研究单个 Aβ 斑块的鞘脂微环境并阐明斑块相关的鞘脂变化。使用多变量数据分析来询问 IMS 数据，以根据脂质化学特征识别病理相关的解剖特征。这种方法揭示了明显位于皮质和海马沉积物中的鞘脂种类，其 Aβ 身份通过荧光淀粉样蛋白染色和免疫组织化学进一步验证。随后对光谱数据的多变量统计分析揭示了神经节苷脂和神经酰胺种类显着定位于 Aβ 阳性斑块，同时伴有硫苷脂的明显局部减少。这些与斑块相关的鞘脂水平变化暗示了鞘脂代谢在 Aβ 斑块病理学和 AD 发病机制中的功能作用。总而言之，所提供的数据强调了成像质谱法作为探测 AD 病理学中与 Aβ 斑块相关的脂质变化的有力方法的潜力。
The major pathological hallmarks of Alzheimer’s disease (AD) are the progressive aggregation and accumulation of beta-amyloid (Aβ) and hyperphosphorylated tau protein into neurotoxic deposits. Aβ aggregation has been suggested as the critical early inducer, driving the disease progression. However, the factors that promote neurotoxic Aβ aggregation remain elusive. Imaging mass spectrometry (IMS) is a powerful technique to comprehensively elucidate the spatial distribution patterns of lipids, peptides, and proteins in biological tissue sections. In the present study, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS)-based imaging was used on transgenic Alzheimer’s disease mouse (tgArcSwe) brain tissue to investigate the sphingolipid microenvironment of individual Aβ plaques and elucidate plaque-associated sphingolipid alterations. Multivariate data analysis was used to interrogate the IMS data for identifying pathologically relevant, anatomical features based on their lipid chemical profile. This approach revealed sphingolipid species that distinctly located to cortical and hippocampal deposits, whose Aβ identity was further verified using fluorescent amyloid staining and immunohistochemistry. Subsequent multivariate statistical analysis of the spectral data revealed significant localization of gangliosides and ceramides species to Aβ positive plaques, which was accompanied by distinct local reduction of sulfatides. These plaque-associated changes in sphingolipid levels implicate a functional role of sphingolipid metabolism in Aβ plaque pathology and AD pathogenesis. Taken together, the presented data highlight the potential of imaging mass spectrometry as a powerful approach for probing Aβ plaque-associated lipid changes underlying AD pathology.