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

• 批准号: 10370874
• 负责人: DAVID EISENBERG
• 金额: $ 106.84万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370874
• 关键词: 3-Dimensional; Acquired Immunodeficiency Syndrome; Address; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease test; American; Amyloid beta-Protein; Amyloidosis; Antibodies; Autopsy; Brain; Cells; Complex; Cryoelectron Microscopy; Data Collection; Dementia; Development; Disease; Drug Binding Site; Drug Design; Electron Microscopy; Epigallocatechin Gallate; Etiology; Exhibits; HIV; Human; Knowledge; Learning; Ligands; Malignant Neoplasms; Mus; Nature; Negative Staining; Nerve Degeneration; Organoids; Pathology; Pharmaceutical Preparations; Property; Proteins; Research Personnel; Resolution; Science; Structure; Tauopathies; Testing; Vacuum; Work; X ray diffraction analysis; abeta oligomer; amyloid structure; base; brain behavior; cell type; cytotoxic; design; drug candidate; drug testing; efficacy evaluation; electrical property; frontier; improved; inhibitor; mouse model; nanoparticle; pharmacophore; protein aggregation; reconstruction; screening; small molecule; tau Proteins; tau aggregation; tau mutation; tool

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. From the recent near-atomic structure of Tau fibrils extracted from the autopsied brain of an Alzheimer’s patient, the drug-binding site (or pharmacophore) has been determined for a fibril-disaggregatng compound. By screening compounds that fit the pharmacophore, new Tau disaggregants have been discovered. These disaggregants dissolve AD-brain Tau fibrils, but do not produce toxic products. From further cycles of structure determination of complexes of Tau fibrils with the new disaggregants, followed by compound screening, safe and effective compounds will be sought to reverse the toxic aggregation of Tau in the brain. Synthetic chemist co-Investigator UCLA Prof. Patrick Harran will collaborate to apply a similar approach to discover complexes of disaggregants with brain-penetrant nanoparticles. 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 than fibrils of the same protein. Oligomers of different fibril-forming proteins share structural similarities in that particular antibodies (A11 & M204) recognize them, but not their corresponding fibrils. The transient nature of oligomers has defeated previous attempts to learn their atomic structures, but our lab has recently discovered a monoclonal Fab that extracts fairly homogeneous oligomers of Tau from AD brains and stabilizes them long enough to make grids suitable for cryoEM structure determination. Preliminary micrographs suggest that antibody ligands permit alignment of beta-amyloid oligomers for cryoEM determination of structure, which may serve subsequently for design of inhibitors and disaggregants. Aim 3 proposes tests of AD drugs in “mini-brains” which are grown in the lab of our co-Investigator UCLA Prof. Novitch. These organoids are 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 can be tested in them. If successful, this approach can provide a new avenue for testing Alzheimer’s drugs prior to human trials. For comparison, our inhibitors and disaggregants will also be assessed in a mouse model of tauopathy.

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 由于进步 衍射和冷冻。蛋白质tau的聚集与痴呆症的发作密切相关。从 从阿尔茨海默氏症患者的尸体大脑中提取的tau原纤维的近乎原子结构， 已经确定了针对原纤维 - 脱落化合物的药物结合位点（或药效实践）。经过 已经发现了适合药效团的筛选化合物，新的Tau分类剂已被发现。这些 分解剂会溶解Ad-Brain tau纤维，但不会产生有毒产品。从进一步的周期 与新的脱落剂的tau原纤维复合物的结构测定，然后是化合物 筛选，将感觉到安全有效的化合物，以逆转Tau的有毒聚集 脑。合成化学家共同投资者UCLA教授帕特里克·哈兰（Patrick Harran）将合作应用类似 发现与脑胶纳米颗粒分裂剂的复合物的方法。 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 细胞毒性比同一蛋白质的原纤维。不同纤维形成蛋白的低聚物共享结构 该特定抗体（A11＆M204）的相似性识别它们，但不能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学习其原子结构的尝试，但是我们的 实验室最近发现了一种单克隆工厂，从AD中提取tau的均匀低聚物 大脑并稳定它们的时间足够长，以使网格适合冷冻结构测定。 初步显微照片表明抗体配体允许对齐β-淀粉样蛋白低聚物的对齐 冷冻确定结构，后来可以用于设计抑制剂和 分类。 AIM 3建议在我们的共同投资者UCLA实验室中生长的“迷你脑”中的AD药物测试 诺维奇教授。这些类器官是BB的大小，但显示了实际的结构和电气特性 人的大脑。它们是由人类细胞制成的，显示了细胞类型和电气消息传递 人的大脑。初步工作表明这些迷你脑部可以感染tau病理学，现在 我们各种候选药物干扰总tau的扩散和损害的能力 可以在其中测试。如果成功，这种方法可以为测试阿尔茨海默氏症的药物提供新的途径 在进行人类试验之前。为了进行比较，我们的抑制剂和分裂剂也将在小鼠中进行评估 tauopathy的模型。