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Towards Treatment of Alzheimer’s Disease by Targeting Pathogenic Tau and Beta-Amyloid Structures

通过靶向致病性 Tau 和 β-淀粉样蛋白结构来治疗阿尔茨海默病

基本信息

批准号：
10330046
负责人：
DAVID EISENBERG
金额：
$ 107.56万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10330046
关键词：
Acquired Immunodeficiency Syndrome Address Affinity Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease test American Amyloid Amyloid Fibrils Amyloid beta-Protein Amyloidosis Antibodies Autopsy Binding Binding Sites Brain Cells Clinic Collaborations Complex Cryoelectron Microscopy Dementia Development Disease Drug Design Effectiveness Electron Microscopy Etiology Exhibits HIV Human Knowledge Learning Malignant Neoplasms Masks Mass Spectrum Analysis Methods Modeling Mole the mammal Molecular Molecular Structure Mus Nature Nerve Degeneration Organoids Pathology Peptides Pharmaceutical Preparations Phosphorylation Post-Translational Protein Processing Proteins Role Science Specificity Structure Testing Translations United States National Institutes of Health Vacuum Weight Work X ray diffraction analysis abeta accumulation abeta oligomer amyloid structure base brain behavior cell type cofactor cytotoxic design drug candidate drug testing electrical property frontier improved inhibitor/antagonist interest neuron loss prophylactic protein aggregation small molecule tau Proteins tau aggregation tau mutation tau phosphorylation tau-1 tool

项目摘要

Project Summary Aim 1 addresses the dearth of drugs for dementia, by structure-based drug design. This approach, so fruitful for treating cancer and HIV-AIDS, is opening for Alzheimer’s Disease (AD) because of advances in diffraction and cryoEM. Aggregation of protein tau is strongly correlated with the onset of dementia. Based on atomic structures, 9 inhibitors of tau aggregation have been designed. Aim 1 proposes determination of the atomic structure of one of these inhibitors on the tip of tau fibrils extracted from the autopsied brain of an AD patient. By binding to fibril tips, our designed inhibitors halt “seeding” of new tau fibrils in connected cells. This atomic structure will reveal how to increase the affinity and specificity of the inhibitor. Aim 1 will also focus on the discovery of the identity and binding sites on tau of molecular factors that drive its aggregation. These structures will enable design of small molecules and peptides that mask the binding site, thereby interfering with factor binding, and hence producing prophylactic drugs for AD. The same approach will visualize binding sites of post-translational modifications of tau, including phosphorylation, offering a related strategy for drug design. Aim 2 proposes to fill the vacuum of knowledge of the structures of small aggregates of tau and beta- amyloid, known as oligomers. Numerous studies of others provide evidence that oligomers are more cytotoxic on a weight basis (but not a mole basis) than fibrils of the same protein. And, somewhat mysteriously, oligomers of different fibril-forming proteins share structural similarities in that a particular antibody (A11) recognizes them, but not their corresponding fibrils. The transient nature of oligomers has defeated previous attempts to learn their atomic structures, but fortunately our collaborators in the Kayed and Raskatov labs have found methods to stabilize oligomers of tau and beta-amyloid, respectively, long enough for us to make grids suitable for cryoEM structure determination. Preliminary micrographs are encouraging. Aim 3 proposes tests of AD drugs in “mini-brains” which are grown in the lab of our collaborator UCLA Prof. Novitch. These organoids are about the size of a BB yet display structure and electrical properties of actual human brains. They are made from human cells and display the cell types and electrical messaging of human brains. Preliminary work shows these mini-brains can be infected with tau pathology, and now the ability of our various drug candidates to interfere with the spreading and damage of aggregated tau will be tested in them. If successful, this approach can provide a new avenue for testing Alzheimer’s drugs prior to human trials.

项目摘要目标1通过基于结构的药物设计解决痴呆症药物的缺乏。这种方法，所以在治疗癌症和艾滋病毒/艾滋病方面卓有成效，由于技术进步，正在为阿尔茨海默病（AD）开辟道路在衍射和冷冻电镜中。tau蛋白的聚集与痴呆的发作密切相关。基于原子结构，已经设计了9种tau聚集抑制剂。目标1建议在从所述细胞中提取的tau原纤维尖端上这些抑制剂之一的原子结构的测定 AD患者的尸检大脑通过与纤维尖端结合，我们设计的抑制剂阻止了新的连接细胞中的tau纤维。这种原子结构将揭示如何增加亲和力和特异性的抑制剂。Aim 1还将集中于发现tau蛋白的身份和结合位点，驱动其聚集的分子因素。这些结构将使设计小分子和掩蔽结合位点的肽，从而干扰因子结合，并因此产生 AD的预防药物。同样的方法将可视化翻译后的结合位点。 tau蛋白的修饰，包括磷酸化，为药物设计提供了相关策略。目标2提出填补tau和β-小聚集体结构知识的真空淀粉样蛋白，称为低聚物。许多其他研究提供的证据表明，低聚物是更多的在重量基础上（但不是摩尔基础上）比相同蛋白质的原纤维具有细胞毒性。而且，神秘的是，不同纤维形成蛋白的寡聚体在结构上有着相似性，抗体（A11）识别它们，但不识别它们相应的原纤维。低聚物的瞬时性质已经击败了以前试图了解它们的原子结构，但幸运的是，我们的合作者在 Kayed和Raskatov实验室已经找到了稳定tau和β-淀粉样蛋白寡聚体的方法，分别，足够长的时间，我们使网格适用于cryoEM结构确定。初步显微照片令人鼓舞。目标3提出在我们的合作者加州大学洛杉矶分校的实验室中培养的“迷你大脑”中测试AD药物教授诺维奇这些类器官的大小约为BB，但显示出结构和电特性真实的人脑它们由人体细胞制成，显示细胞类型和电人类大脑的信息传递。初步工作表明，这些迷你大脑可以感染tau蛋白病理学，现在我们的各种候选药物的能力，以干扰传播，将在其中测试聚集的tau的损伤。如果成功，这种方法可以提供一种新的途径，在人体试验前测试阿尔茨海默病药物