Tetramodal Chemical Imaging Delineates the Lipid-Amyloid Peptide Interplay at Single Plaques in Transgenic Alzheimer's Disease Models.
Tetramodal Chemical Imaging Delineates the Lipid-Amyloid Peptide Interplay at Single Plaques in Transgenic Alzheimer's Disease Models.
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DOI：
10.1021/acs.analchem.2c05302
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发表时间：
2023-03-14
影响因子：
7.4
通讯作者：
Hanrieder, Joerg
中科院分区：
文献类型：
--
作者：
Ge, Junyue;Koutarapu, Srinivas;Jha, Durga;Dulewicz, Maciej;Zetterberg, Henrik;Blennow, Kaj;Hanrieder, Joerg
β-淀粉样蛋白（Aβ）斑块是阿尔茨海默病（AD）最显著的病理组织学特征之一。然而，将Aβ与AD发病机制联系起来的确切致病机制仍不完全清楚。淀粉样蛋白靶向药物治疗的最新进展突出了Aβ聚集与理解AD发病机制的分子基础的关键相关性。我们开发了一种新的，集成的，四峰化学成像模式，用于从单个组织切片获取三峰质谱成像（MSI）和交错荧光显微镜。我们使用这种方法全面研究了两种不同AD小鼠模型（tgAPPSWe和tgAPPArcSwe）中单个斑块处的脂质-A β相关性，这些模型具有不同程度的影响淀粉样蛋白聚集的内在特性。多模态成像数据和多变量数据分析的整合确定了两种小鼠模型中斑块相关脂质和肽定位的特征模式。使用结构敏感性淀粉样蛋白探针的相关荧光显微镜鉴定了斑块内结构特异性脂质和Aβ模式，包括Aβ 1-40和Aβ 1-42沿着神经节苷脂（GM）、磷酸肌醇（PI）、结合神经酰胺（CerP和PE-Cer）和溶血磷脂（LPC、LPA和LPI）。所有模式的单斑块相关性分析进一步揭示了这些不同的脂质物质如何与斑块异质性中的Aβ肽沉积相关，表明这些脂质分别在斑块生长和淀粉样蛋白纤维化中发挥不同作用。此处，结合神经酰胺物质与Aβ核心形成相关，表明其参与初始斑块播种或淀粉样蛋白成熟。相反，LPI和PI仅与一般斑块生长相关。此外，GM 1和LPC与Aβ的持续沉积和成熟相关。结果突出了这种综合多模态成像方法的潜力，并在淀粉样蛋白病中实现了不同的脂质。
Beta-amyloid (Aβ) plaque pathology is one of the most prominent histopathological feature of Alzheimer’s disease (AD). The exact pathogenic mechanisms linking Aβ to AD pathogenesis remain however not fully understood. Recent advances in amyloid-targeting pharmacotherapies highlight the critical relevance of Aβ aggregation for understanding the molecular basis of AD pathogenesis. We developed a novel, integrated, tetramodal chemical imaging paradigm for acquisition of trimodal mass spectrometry imaging (MSI) and interlaced fluorescent microscopy from a single tissue section. We used this approach to comprehensively investigate lipid–Aβ correlates at single plaques in two different mouse models of AD (tgAPPSwe and tgAPPArcSwe) with varying degrees of intrinsic properties affecting amyloid aggregation. Integration of the multimodal imaging data and multivariate data analysis identified characteristic patterns of plaque-associated lipid- and peptide localizations across both mouse models. Correlative fluorescence microscopy using structure-sensitive amyloid probes identified intra-plaque structure-specific lipid- and Aβ patterns, including Aβ 1–40 and Aβ 1–42 along with gangliosides (GM), phosphoinositols (PI), conjugated ceramides (CerP and PE-Cer), and lysophospholipids (LPC, LPA, and LPI). Single plaque correlation analysis across all modalities further revealed how these distinct lipid species were associated with Aβ peptide deposition across plaque heterogeneity, indicating different roles for those lipids in plaque growth and amyloid fibrillation, respectively. Here, conjugated ceramide species correlated with Aβ core formation indicating their involvement in initial plaque seeding or amyloid maturation. In contrast, LPI and PI were solely correlated with general plaque growth. In addition, GM1 and LPC correlated with continuous Aβ deposition and maturation. The results highlight the potential of this comprehensive multimodal imaging approach and implement distinct lipids in amyloidogenic proteinopathy.
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影响因子：
16.2
作者：
Kim, Jungsu;Basak, Jacob M.;Holtzman, David M.
通讯作者：
Holtzman, David M.
影响因子：
4.8
作者：
Canals, Daniel;Roddy, Patrick;Hannun, Yusuf A.
通讯作者：
Hannun, Yusuf A.
影响因子：
5
作者：
Kaya, Ibrahim;Brinet, Dimitri;Hanrieder, Jorg
通讯作者：
Hanrieder, Jorg
影响因子：
5
作者：
Kaya I;Brinet D;Michno W;Syvänen S;Sehlin D;Zetterberg H;Blennow K;Hanrieder J
通讯作者：
Hanrieder J
影响因子：
15.1
作者：
Benitez DP;Jiang S;Wood J;Wang R;Hall CM;Peerboom C;Wong N;Stringer KM;Vitanova KS;Smith VC;Joshi D;Saito T;Saido TC;Hardy J;Hanrieder J;De Strooper B;Salih DA;Tripathi T;Edwards FA;Cummings DM
通讯作者：
Cummings DM