Department of Chemistry and Molecular Biology , University of Gothenburg , Kemivägen 10 , 405 30 Gothenburg , Sweden.
Department of Psychiatry and Neurochemistry , Sahlgrenska Academy at the University of Gothenburg , Mölndal Hospital, House V3, 43180 Mölndal , Sweden.
ACS Chem Neurosci. 2018 Jul 18;9(7):1802-1817. doi: 10.1021/acschemneuro.8b00121. Epub 2018 May 4.
Senile plaques formed by aggregated amyloid β peptides are one of the major pathological hallmarks of Alzheimer's disease (AD) which have been suggested to be the primary influence triggering the AD pathogenesis and the rest of the disease process. However, neurotoxic Aβ aggregation and progression are associated with a wide range of enigmatic biochemical, biophysical and genetic processes. MALDI imaging mass spectrometry (IMS) is a label-free method to elucidate the spatial distribution patterns of intact molecules in biological tissue sections. In this communication, we utilized multimodal MALDI-IMS analysis on 18 month old transgenic AD mice (tgArcSwe) brain tissue sections to enhance molecular information correlated to individual amyloid aggregates on the very same tissue section. Dual polarity MALDI-IMS analysis of lipids on the same pixel points revealed high throughput lipid molecular information including sphingolipids, phospholipids, and lysophospholipids which can be correlated to the ion images of individual amyloid β peptide isoforms at high spatial resolutions (10 μm). Further, multivariate image analysis was applied in order to probe the multimodal MALDI-IMS data in an unbiased way which verified the correlative accumulations of lipid species with dual polarity and Aβ peptides. This was followed by the lipid fragmentation obtained directly on plaque aggregates at higher laser pulse energies which provided tandem MS information useful for structural elucidation of several lipid species. Majority of the amyloid plaque-associated alterations of lipid species are for the first time reported here. The significance of this technique is that it allows correlating the biological discussion of all detected plaque-associated molecules to the very same individual amyloid plaques which can give novel insights into the molecular pathology of even a single amyloid plaque microenvironment in a specific brain region. Therefore, this allowed us to interpret the possible roles of lipids and amyloid peptides in amyloid plaque-associated pathological events such as focal demyelination, autophagic/lysosomal dysfunction, astrogliosis, inflammation, oxidative stress, and cell death.
由聚集的淀粉样 β 肽形成的老年斑是阿尔茨海默病 (AD) 的主要病理特征之一，据认为是触发 AD 发病机制和疾病其余过程的主要影响因素。然而，神经毒性 Aβ 聚集和进展与广泛的神秘生化、生物物理和遗传过程有关。基质辅助激光解吸电离成像质谱 (MALDI-IMS) 是一种无标记的方法，可以阐明生物组织切片中完整分子的空间分布模式。在本通讯中，我们利用多模态 MALDI-IMS 分析对 18 个月大的转基因 AD 小鼠 (tgArcSwe) 脑组织切片进行分析，以增强与同一组织切片上单个淀粉样蛋白聚集相关的分子信息。对同一像素点的脂质进行双极性 MALDI-IMS 分析，揭示了包括鞘脂、磷脂和溶血磷脂在内的高通量脂质分子信息，这些信息可以与单个淀粉样 β 肽异构体的离子图像相关联，具有高空间分辨率 (10 μm)。此外，还应用了多元图像分析方法，以便以无偏的方式探测多模态 MALDI-IMS 数据，该方法验证了脂质种类与双极性和 Aβ 肽的相关性积累。接着，在更高的激光脉冲能量下，直接在斑块聚集体上获得脂质碎片，提供了有用的串联 MS 信息，有助于几种脂质种类的结构阐明。大多数与淀粉样斑块相关的脂质种类的改变都是首次在这里报道。该技术的意义在于，它允许将所有检测到的斑块相关分子的生物学讨论与同一单个淀粉样斑块相关联，从而可以深入了解特定脑区中甚至单个淀粉样斑块微环境的分子病理学。因此，这使我们能够解释脂质和淀粉样肽在与淀粉样斑块相关的病理事件（如局灶性脱髓鞘、自噬/溶酶体功能障碍、星形胶质细胞增生、炎症、氧化应激和细胞死亡）中的可能作用。
