Correlative Chemical Imaging Identifies Amyloid Peptide Signatures of Neuritic Plaques and Dystrophy in Human Sporadic Alzheimer's Disease.
Correlative Chemical Imaging Identifies Amyloid Peptide Signatures of Neuritic Plaques and Dystrophy in Human Sporadic Alzheimer's Disease.
复制标题
相关化学成像识别人类散发性阿尔茨海默病神经炎斑块和营养不良的淀粉样肽特征。
DOI：
10.1089/brain.2022.0047
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发表时间：
2023
影响因子：
3.4
通讯作者：
Hanrieder,Jörg
中科院分区：
文献类型：
--
作者：
Koutarapu,Srinivas;Ge,Junyue;Jha,Durga;Blennow,Kaj;Zetterberg,Henrik;Lashley,Tammaryn;Michno,Wojciech;Hanrieder,Jörg
目的：阿尔茨海默病（Alzheimer's disease，AD）是最常见的神经退行性疾病。AD的主要散发形式与年龄相关，但其潜在的致病机制仍不完全清楚。目前对抗该疾病的努力集中在主要的病理学标志上，特别是β-淀粉样蛋白（Aβ）斑块病理学。根据淀粉样蛋白级联假说，Aβ是AD发病机制的关键早期启动子。斑块病理学是非常异质性的，其中一个子集的斑块，神经炎斑块（NPs），被认为是最神经毒性的渲染其深入表征了解Aβ pathogenicity.Methods的化学特征，以描绘特定的NP类型，我们研究了老年Aβ病理学在死后，人类散发性AD脑使用先进的相关生化成像的基础上，免疫荧光（IF）显微镜和质谱imaging（MSI.Results）：免疫染色引导的MSI确定不同的Aβ签名的NPs，其特征是增加Aβ1-42（ox）和Aβ2-42。此外，与营养不良的标志物（reticulon 3 [RTN 3]）的相关性确定了关键的Aβ种类，这两个描绘NPs和显示关联neuritic dystrophy.Conclusion：总之，这些相关的成像数据揭示了复杂的生化结构的NPs和相关的营养不良的神经突。这些反过来又是疾病修饰治疗策略的明显靶点，以及Aβ致病性的新生物标志物。
Objective:Alzheimer's disease (AD) is the most common neurodegenerative disease. The predominantly sporadic form of AD is age-related, but the underlying pathogenic mechanisms remain not fully understood. Current efforts to combat the disease focus on the main pathological hallmarks, in particular beta-amyloid (Aβ) plaque pathology. According to the amyloid cascade hypothesis, Aβ is the critical early initiator of AD pathogenesis. Plaque pathology is very heterogeneous, where a subset of plaques, neuritic plaques (NPs), are considered most neurotoxic rendering their in-depth characterization essential to understand Aβ pathogenicity.Methods:To delineate the chemical traits specific to NP types, we investigated senile Aβ pathology in the postmortem, human sporadic AD brain using advanced correlative biochemical imaging based on immunofluorescence (IF) microscopy and mass spectrometry imaging (MSI).Results:Immunostaining-guided MSI identified distinct Aβ signatures of NPs characterized by increased Aβ1–42(ox) and Aβ2–42. Moreover, correlation with a marker of dystrophy (reticulon 3 [RTN3]) identified key Aβ species that both delineate NPs and display association with neuritic dystrophy.Conclusion:Together, these correlative imaging data shed light on the complex biochemical architecture of NPs and associated dystrophic neurites. These in turn are obvious targets for disease-modifying treatment strategies, as well as novel biomarkers of Aβ pathogenicity.