Chemical imaging of evolving amyloid plaque pathology and associated Aβ peptide aggregation in a transgenic mouse model of Alzheimer's disease
Chemical imaging of evolving amyloid plaque pathology and associated Aβ peptide aggregation in a transgenic mouse model of Alzheimer's disease
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DOI：
10.1111/jnc.14888
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发表时间：
2019-11-06
影响因子：
4.7
通讯作者：
Hanrieder, Jorg
中科院分区：
文献类型：
--
作者：
Michno, Wojciech;Wehrli, Patrick;Hanrieder, Jorg
阿尔茨海默病（AD）病理学的主要标志之一是细胞外淀粉样蛋白β（A β）斑块的形成。虽然A β已被认为是关键的诱导和潜在的驱动疾病，AD发病机制的分子基础仍在争论中。细胞外A β斑块病理学表现为不同A β肽的聚集，导致形态学上不同的斑块形态型，主要包括弥漫性和核心老年斑。由于斑块病理学早在任何临床症状发生之前就已沉淀，因此靶向A β聚集过程为早期干预提供了有希望的靶点。然而，A β物种何时、何地以及如何聚集并形成斑块的事件链仍不清楚。本研究的目的是调查潜在的基质辅助激光解吸/电离成像质谱作为一种工具，研究不断变化的病理学在转基因小鼠模型的AD。为此，我们使用了一种新兴的化学成像模式-基质辅助激光解吸/电离成像质谱法-允许在单个斑块水平上描绘具有特异性的A β聚集。我们发现，斑块形成首先发生在皮质区域，这些年轻的斑块含有更高水平的42个氨基酸长的A β（A β 1-42）。发现斑块成熟的特征在于A β 1-40沉积的相对增加，这与这些斑块的核心形态的出现有关。最后，其他C端截短的A β物质（A β 1-38和A β 1-39）显示出与A β 1-40相似的聚集模式，表明这些物质具有相似的聚集特征。这些结果表明，初始斑块形成是由A β 1-42接种的; A β 1-40沉积以及其他C端修饰的A β物质沉积后，斑块成熟的过程。
One of the major hallmarks of Alzheimer's disease (AD) pathology is the formation of extracellular amyloid beta (A beta) plaques. While A beta has been suggested to be critical in inducing and, potentially, driving the disease, the molecular basis of AD pathogenesis is still under debate. Extracellular A beta plaque pathology manifests itself upon aggregation of distinct A beta peptides, resulting in morphologically different plaque morphotypes, including mainly diffuse and cored senile plaques. As plaque pathology precipitates long before any clinical symptoms occur, targeting the A beta aggregation processes provides a promising target for early interventions. However, the chain of events of when, where and what A beta species aggregate and form plaques remains unclear. The aim of this study was to investigate the potential of matrix-assisted laser desorption/ionization imaging mass spectrometry as a tool to study the evolving pathology in transgenic mouse models for AD. To that end, we used an emerging, chemical imaging modality - matrix-assisted laser desorption/ionization imaging mass spectrometry - that allows for delineating A beta aggregation with specificity at the single plaque level. We identified that plaque formation occurs first in cortical regions and that these younger plaques contain higher levels of 42 amino acid-long A beta (A beta 1-42). Plaque maturation was found to be characterized by a relative increase in deposition of A beta 1-40, which was associated with the appearance of a cored morphology for those plaques. Finally, other C-terminally truncated A beta species (A beta 1-38 and A beta 1-39) exhibited a similar aggregation pattern as A beta 1-40, suggesting that these species have similar aggregation characteristics. These results suggest that initial plaque formation is seeded by A beta 1-42; a process that is followed by plaque maturation upon deposition of A beta 1-40 as well as deposition of other C-terminally modified A beta species.