Multimodal Chemical Imaging of Amyloid Plaque Polymorphism Reveals Aβ Aggregation Dependent Anionic Lipid Accumulations and Metabolism
Multimodal Chemical Imaging of Amyloid Plaque Polymorphism Reveals Aβ Aggregation Dependent Anionic Lipid Accumulations and Metabolism
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DOI：
10.1021/acs.analchem.8b01361
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发表时间：
2018-07-03
影响因子：
7.4
通讯作者：
Hanrieder, Jorg
中科院分区：
文献类型：
--
作者：
Michno, Wojciech;Kaya, Ibrahim;Hanrieder, Jorg
淀粉样斑块的形成是阿尔茨海默病（AD）的主要病理标志之一，被认为是驱动疾病发病机制的关键因素。有趣的是，在表现出淀粉样蛋白病理但认知正常的患者中，A β沉积物主要呈弥漫性形态，这表明有芯斑块的形成主要与认知功能恶化和AD的发病有关。对于A β转化为神经毒性聚集体的分子机制以及AD中观察到的主要核沉积，我们知之甚少。A - β斑块的结构多样性，包括核/致密和弥漫性，可能与它们独特的A - β特征和其他化学物质（包括神经元脂质）有关。我们开发了一种新的化学成像范例，结合了基质辅助激光解吸/电离成像质谱（MALDI IMS）和荧光淀粉样蛋白染色。这种多模态成像方法被用来探测转基因AD小鼠（tgAPP(Swe)）中与结构斑块异质性相关的脂质化学，并与随后通过激光显微解剖和免疫沉淀-质谱测定的A β谱相关。多变量图像分析显示，神经酰胺及其匹配的代谢物分别在单个斑块中逆定位于弥漫性和核心结构。此外，与AD发病机制有关的磷脂酰肌醇被发现定位于弥漫性A β结构，并与A β 1-42相关。此外，与神经炎症有关的溶血磷脂在所有A β沉积物中均增加。这些结果支持了先前关于脂质紊乱在阿尔茨海默病病理生理和相关鞘脂加工中的重要性的临床发现。这些数据突出了多模态成像作为一种探索神经病理机制的强大技术的潜力。
Amyloid plaque formation constitutes one of the main pathological hallmarks of Alzheimer's disease (AD) and is suggested to be a critical factor driving disease pathogenesis. Interestingly, in patients that display amyloid pathology but remain cognitively normal, A beta deposits are predominantly of diffuse morphology suggesting that cored plaque formation is primarily associated with cognitive deterioration and AD pathogenesis. Little is known about the molecular mechanism responsible for conversion of monomeric A beta into neurotoxic aggregates and the predominantly cored deposits observed in AD. The structural diversity among A beta plaques, including cored/compact- and diffuse, may be linked to their distinct A beta profile and other chemical species including neuronal lipids. We developed a novel, chemical imaging paradigm combining matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) and fluorescent amyloid staining. This multimodal imaging approach was used to probe the lipid chemistry associated with structural plaque heterogeneity in transgenic AD mice (tgAPP(Swe)) and was correlated to A beta profiles determined by subsequent laser microdissection and immunoprecipitation-mass spectrometry. Multivariate image analysis revealed an inverse localization of ceramides and their matching metabolites to diffuse and cored structures within single plaques, respectively. Moreover, phosphatidylinositols implicated in AD pathogenesis, were found to localize to the diffuse A beta structures and correlate with A beta 1-42. Further, lysophospholipids implicated in neuroinflammation were increased in all A beta deposits. The results support previous clinical findings on the importance of lipid disturbances in AD pathophysiology and associated sphingolipid processing. These data highlight the potential of multimodal imaging as a powerful technology to probe neuropathological mechanisms.