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

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

展开

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 AIM 1通过基于结构的药物设计来解决痴呆症药物的死亡。这种方法，所以由于进展在衍射和冷冻中。蛋白质tau的聚集与痴呆症的发作密切相关。基于原子结构，已经设计了9种Tau聚集的抑制剂。目标1提案从从tau原纤维尖端上提取的这些抑制剂之一的原子结构的测定广告患者的大脑尸检。通过与原纤维尖端结合，我们设计的抑制剂停止了新的“播种” 连接细胞中的tau纤维。这种原子结构将揭示如何提高亲和力和特异性抑制剂。 AIM 1还将集中于发现身份和绑定位点的tau 驱动其聚集的分子因子。这些结构将实现小分子的设计和掩盖结合位点的胡椒粉，从而干扰因子结合，从而产生预防药物的AD。相同的方法将可视化翻译后的绑定位点 TAU的修饰，包括磷酸化，为药物设计提供了相关的策略。目标2提案，以填补tau和beta-骨料骨料结构的知识真空淀粉样蛋白，称为低聚物。对其他研究的大量研究提供了证据表明低聚物更多与同一蛋白质的原纤维相比，重量（但不是摩尔）的细胞毒性。而且，有点神秘地，不同原纤维形成蛋白的低聚物具有结构性相似性抗体（A11）识别它们，但不能识别其相应的原纤维。低聚物的瞬时性质已经击败了以前学习其原子结构的尝试，但幸运的是，我们的合作者皮划艇和拉斯卡托夫实验室发现了稳定tau和β-淀粉样蛋白的寡聚物的方法，分别为我们提供适合冷冻结构确定的网格。初步的显微照片令人鼓舞。 AIM 3建议在我们合作者UCLA实验室中种植的“迷你脑”中的AD药物测试诺维奇教授。这些类器官大约是BB的大小，但显示结构和电性能实际的人类大脑。它们是由人类细胞制成的，显示细胞类型和电动人类大脑的信息。初步工作表明这些微型脑子可以被tau感染病理学，现在我们各种候选者干扰扩散的能力总tau的损坏将在其中测试。如果成功，这种方法可以提供新的途径用于在人类试验之前测试阿尔茨海默氏症药物。