Defining native proteoform landscape for amyloid-beta in Alzheimers disease

定义阿尔茨海默病中β淀粉样蛋白的天然蛋白质形态

• 批准号: 9803611
• 负责人: NEIL L KELLEHER
• 金额: $ 290.9万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9803611
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid beta-Protein; Amyloidosis; Animal Model; Binding; Bioinformatics; Biological Assay; Brain; Brain region; Cells; Chemicals; Clinical Data; Communities; Complement; Complex; Consensus; Cryoelectron Microscopy; DNA; Data; Dementia; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Distant; Elements; Environment; Event; Family; Functional disorder; Health; Herpesviridae Infections; Histologic; Human; Immunoassay; In Vitro; Investigation; Knowledge; Ligands; Link; Liquid substance; Mass Spectrum Analysis; Measures; Mediating; Membrane; Meta-Analysis; Metals; Methods; Modeling; Molecular; Molecular Conformation; Mus; Nerve Degeneration; Neurocognitive Deficit; Neurofibrillary Tangles; Neurosciences; Onset of illness; Oxidation-Reduction; Pathogenesis; Pathologic; Pathology; Patients; Pattern; Peptides; Phenotype; Play; Population; Post-Translational Protein Processing; Procedures; Protein Analysis; Protein Chemistry; Proteins; Proteome; Proteomics; RNA; Reporting; Research; Role; Sampling; Science; Shapes; Signal Transduction; Solubility; Stream; Structural defect; Structure; Synapses; Technology; Testing; Therapeutic antibodies; Toxic effect; Work; X-Ray Crystallography; abeta oligomer; base; cofactor; conformer; crosslink; data acquisition; data mining; demented; experience; human subject; imaging probe; improved; in vivo; innovation; insight; knowledge base; macromolecular assembly; monomer; multidisciplinary; neuroinflammation; neurotoxicity; nonhuman primate; physiologic model; protein complex; screening; spatiotemporal; stem; targeted treatment; temporal measurement; tool; virtual

Abstract Distinct amyloid-beta (Aβ) conformers such as peptides, oligomers (AβOs), and fibrils have long been targets studied for the cause, diagnosis and treatment of Alzheimer’s disease (AD). Spatiotemporal spreading of AβOs is theorized to underly AD progression; however, because of significant polydispersity, no consensus has been reached into which AβO structural elements or size distribution leads to potent neurotoxicity. Indeed, reports suggest some Aβ species may play a protective role in the CNS, through a mechanism in which herpesviridae infection promotes Aβ amyloidosis. Evidence also suggests Aβ exists in diverse modified proteoforms or associate with cofactors (e.g., metals). The diversification of Aβ monomers may contribute to different rates of Aβ oligomerization, in a manner that results in distinct AβOs populations that trigger synaptic dysfunction. Our work suggests that chemical diversification of Aβ through post-translational modifications (PTMs) and non- covalent interactions (e.g., metals) leads to potentially hundreds of native monomeric Aβ proteoforms. We propose that the compositional makeup of these monomers varies in a manner that is associated with stages and brain regions during AD onset and progression, analogous to the stages established for plaques and tangles by Braak and Braak. A new native Top-down mass spectrometry (nTDMS) procedure pioneered by our team has provided us momentum to test this hypothesis by providing a sensitive measure of the native Aβ proteoforms that exist in AβOs of virtually any size. The assay reads the Aβ PTM-status and characterizes bound co-factors, including metals, in a single detection event. Aim 1 will describe the spatial pattern of native Aβ proteoforms in demented patients and animal models relative to controls. Data mining will describe signatures of Aβ related by covalent PTMs or non-covalent interactions, correlating the signatures to pathological co-variables. Aim 2 will utilize data mining to define proteoform signatures that associate with cellular phenotypes (e.g., synapse binding and neuroinflammation). Aim 3 will describe the temporal variability of Aβ proteoforms relative to distinct neuropathological features in animal models. Partnering with neuroscientists, in Aim 4 we will create a Proteinopathy Proteoform Knowledgebase that aggregates proteoform data in a manner that links subsets of proteoforms to disease relevant phenotypes (e.g., Aβ pathologies) or other clinical data. Overall, our work will provide fundamental insights on spatiotemporal signaling leading to dementia, and will inform many Aβ research tracks, including hypothesis testing in relation to in vivo targeting of Aβ imaging probes or diagnostic or therapeutic antibodies.

抽象的 不同的淀粉样β（Aβ）构象体，例如肽，低聚物（AβOS）和原纤维长期以来一直是靶标 研究了阿尔茨海默氏病（AD）的原因，诊断和治疗。 AβOS的时空扩散 从理论上讲是基本的广告进展；但是，由于具有重要的多分散性，尚无共识 AβO结构元素或大小分布导致潜在的神经毒性。确实，报告 建议某些Aβ物种可以通过疱疹性科中的机制在中枢神经系统中起受保护的作用 感染促进Aβ淀粉样变性。证据还表明，在潜水员修饰的蛋白质成型或 与辅因子（例如金属）结合。 Aβ单体的多元化可能有助于不同的速率 Aβ寡聚，以导致触发突触功能障碍的不同AβOS种群的方式。我们的 工作表明，通过翻译后修饰（PTM）和非 - 共价相互作用（例如金属）可能导致数百种天然单体Aβ蛋白质成型。我们 建议这些单体的复合构成与阶段相关的方式 AD发作和进展过程中的大脑区域，类似于斑块和缠结的阶段 由Braak和Braak撰写。我们团队开创的新型本地自上而下的质谱（NTDMS）程序 通过提供天然Aβ蛋白质成型的敏感测量，为我们提供了测试这一假设的动力 这几乎存在于任何大小的AβOS中。该测定读取AβPTM状态和字符结合的副因素， 包括金属，在一个检测事件中。 AIM 1将描述天然Aβ蛋白相的空间模式 相对于对照组的痴呆患者和动物模型。数据挖掘将描述Aβ的特征 共价PTM或非共价相互作用，将签名与病理共同变异相关。 AIM 2意志 利用数据挖掘来定义与细胞表型相关的蛋白质成型特征（例如，突触结合 和神经炎症）。 AIM 3将描述相对于不同的Aβ蛋白成型的暂时变异性 动物模型中的神经病理学特征。与神经科学家合作，在AIM 4中，我们将创建一个 蛋白质病蛋白质成型知识基础，该知识基础以链接的方式汇总蛋白质成型数据 与疾病相关的表型（例如Aβ病理）或其他临床数据的蛋白质成型。总的来说，我们的工作将 提供有关导致痴呆的时空信号传导的基本见解，并将告知许多Aβ研究 轨道，包括与Aβ成像探针的体内靶向靶向的假设检验或诊断或 治疗性抗体。