Water-soluble Abeta and its role in Alzheimer's disease

水溶性 Abeta 及其在阿尔茨海默病中的作用

• 批准号: 9268547
• 负责人: Dominic Martin Walsh
• 金额: $ 35.1万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9268547
• 关键词: AN-1792; Affect; Alzheimer' s Disease; Amino Acid Sequence; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antibodies; Autopsy; Biochemical; Biological Assay; Biological Process; Brain; Brain Diseases; Brain Pathology; Clinical; Cognitive; Complex; Data; Dementia; Disease; Event; Field Flow Fractionation; Genetic; Goals; Hand; Healthcare Systems; Hippocampus (Brain); Human; Immunize; Immunotherapy; Impaired cognition; In Vitro; Individual; Knock-in; Knock-in Mouse; Lead; Learning; Link; Long-Term Potentiation; Mass Spectrum Analysis; Measures; Mediator of activation protein; Memory; Methods; Modification; Molecular Conformation; Molecular Sieve Chromatography; Monitor; Morphology; Nature; Neurobiology; Neurons; Neurotoxins; Pathogenicity; Pathology; Patients; Peptide Vaccines; Peptides; Plasma; Post-Translational Protein Processing; Preparation; Prion Diseases; Protein Fragment; Protein Precursors; Role; Seeds; Senile Plaques; Structure; Symptoms; Synaptic plasticity; Techniques; Testing; Therapeutic; Therapeutic antibodies; Tissues; Toxic effect; Transgenic Organisms; Translations; Uncertainty; Vaccination; Water; amyloidogenesis; aqueous; base; brain tissue; clinical effect; crosslink; demented; effective therapy; experimental study; human tissue; in vivo; monomer; mouse model; neurotoxic; neurotoxicity; protein metabolite; protein oligomer; protein structure; public health relevance; targeted therapy trials; tau phosphorylation

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) represents a personal and societal tragedy that demands an accelerated effort to develop effective therapies. Strong genetic evidence links the amyloid precursor protein (APP) and its proteolytic derivatives to AD. A leading hypothesis proposes that a small amphipathic fragment of APP, amyloid b-protein (Ab), self-associates to form assemblies loosely referred to as "oligomers", and that these trigger a complex pathogenic sequence of events that culminate in dementia. However, the toxic forms of Ab in human brain, and their relationship to disease have not been rigorously studied. Given the unsustainable burden that AD is placing on healthcare systems worldwide, it is essential that scientific doubts about the role of Ab and how it is best targeted are dealt with directly and swiftly. More than a decade ago, we and others proposed that certain non-monomeric, non-fibrillar forms of Ab are potent neurotoxins and may be the precipitating agent in AD. Yet the precise biochemical identity of these "toxic oligomers" remains unclear. Moreover, while the vast bulk of studies of Ab structure and activity have used synthetic Ab peptides, it is now apparent that brain-derived Ab preparations are much more damaging to neurons and much better seeds for amyloidogenesis than are Ab assemblies formed in vitro. We hypothesize that the enhanced toxic activity of brain-derived oligomers is related to the presence of mixtures of different Ab sequences, post-translational modifications and/or formation of covalent cross-links, all of which act to increase the stability of toxic assemblies. s appears to be true in prion diseases, we predict that the size, conformation and stability of Ab assemblies strongly influence their toxic activity. Using aqueous extracts of AD brains, and based on substantial preliminary data, we propose to investigate rigorously: (i) the assembly size, (ii) conformations and (iii) dynamic nature of toxic Ab species. Then we propose to purify them to homogeneity and to elucidate their composition. Throughout our experiments, we will constantly link our physical analyses with measures of neurobiological activity directly relevant to AD. Thereafter, we will analyze postmortem tissue to compare the quantity and quality of toxic oligomers in brains of demented subjects vs. cognitively normal humans with high plaque burdens. Using the same human tissues, we will also measure the levels of other APP fragments to see if any of these better relate to disease than does Ab. Then we will examine brain tissue and plasma from AD patients that received the AN1792 vaccination. The goal of this particular experiment is to ascertain how vaccination affects the levels and forms of Ab in the human brain and whether some immunized patients develop antibodies capable of targeting the toxic oligomers. Finally, from a selection of 20 candidate antibodies in hand, we will identify one that preferentially recognizes toxic oligomers. Then we expect to learn whether it can protect against Ab species in AD mouse models better than does the current lead therapeutic antibody, mAb266.

描述（由申请人提供）：阿尔茨海默氏病（AD）代表了一场个人和社会悲剧，要求加快开发有效疗法的努力。有力的遗传证据将淀粉样蛋白前体蛋白（APP）及其蛋白水解衍生物与AD联系起来。一个主要假设提出，APP，淀粉样蛋白B蛋白（AB）的小两亲性片段，自我关联以松散称为“低聚物”形成组件，并且这些触发了在痴呆症中的良心事件的复杂致病序列。但是，尚未严格研究人类大脑中AB的毒性形式及其与疾病的关系。鉴于广告在全球医疗保健系统上承担的不可持续负担，因此对AB的作用及其最佳目标的科学怀疑至关重要。十多年前，我们和其他人提出，某些非共同的非纤维形式的AB是有效的神经毒素，可能是AD中的沉淀剂。然而，这些“有毒的低聚物”的确切生化身份尚不清楚。此外，虽然对AB结构和活性的大量研究使用了合成的AB肽，但现在很明显，与体外形成的AB组件相比，脑衍生的AB制剂对神经元的损害更大，并且对淀粉样蛋白生成的种子更大。我们假设脑源性低聚物的毒性活性增强与存在不同AB序列的混合物，翻译后修饰和/或共价交叉链接的形成有关，所有这些都起作用，这些作用于增加有毒组装的稳定性。 S在病毒疾病中似乎是正确的，我们预测AB组件的大小，构象和稳定性会强烈影响其毒性活性。使用AD大脑的水提取物，并基于大量的初步数据，我们建议严格研究：（i）组装大小，（ii）构象和（iii）有毒AB物种的动态性质。然后，我们建议将它们净化为同质性并阐明它们的组成。在整个实验中，我们将不断将身体分析与与AD直接相关的神经生物学活动的度量联系起来。此后，我们将分析验尸组织，以比较痴呆受试者大脑中有毒寡聚的数量和质量与具有高斑块负担的认知正常人。使用相同的人体组织，我们还将测量其他APP片段的水平，以查看与疾病相比是否与AB更好地相关。然后，我们将检查接受AN1792疫苗接种的AD患者的脑组织和血浆。该特定实验的目的是确定疫苗接种如何影响人脑中AB的水平和形式，以及某些免疫患者是否会产生能够靶向有毒低聚物的抗体。最后，从手头选择的20种候选抗体中，我们将确定一种 这优先识别有毒的低聚物。然后，我们希望比当前的铅治疗抗体MAB266了解它是否可以更好地保护AD小鼠模型中的AB物种。