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 目的1通过基于结构的药物设计解决痴呆症药物的匮乏问题。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，正在为阿尔茨海默病(AD)打开大门，因为在 衍射和低温电子显微镜。Tau蛋白的聚集与痴呆的发病密切相关。从… 最近从阿尔茨海默氏症患者尸检脑中提取的Tau纤维的近原子结构， 已经确定了一种纤维解聚化合物的药物结合部位(或药效团)。通过 筛选符合药效团的化合物，发现了新的牛磺酸解聚剂。这些 解聚剂可以溶解AD-Brain Tau纤维，但不会产生有毒产物。从进一步的循环中 新型解聚剂与Tau原纤维络合物的结构测定 将寻求安全有效的化合物来逆转牛磺酸在人体内的毒性聚集 大脑。加州大学洛杉矶分校合成化学家共同研究员帕特里克·哈兰教授将合作应用类似的 发现解聚剂与脑穿透纳米粒复合体的方法。 目标2建议填补关于牛磺酸和贝塔的小集合体结构的知识真空。 淀粉样蛋白，称为寡聚体。对其他低聚物的大量研究提供了证据，表明齐聚物比 比相同蛋白质的纤维具有更强的细胞毒性。不同纤维形成蛋白的低聚物具有共同的结构 相似之处在于，特定的抗体(A11和M204)可以识别它们，但不能识别它们对应的纤维。 低聚物的瞬变性质挫败了之前研究其原子结构的尝试，但我们的 实验室最近发现了一种从AD中提取相当均一的Tau寡聚体的单克隆Fab 大脑和稳定它们足够长的时间，使网格适合于低温EM结构确定。 初步的显微照片表明，抗体配体允许β-淀粉样蛋白低聚物对齐 低温电子显微镜对结构的测定，这可能随后用于缓蚀剂和 解聚剂。 Aim 3建议在我们的合作调查员加州大学洛杉矶分校的实验室里培养的“迷你大脑”中测试AD药物 诺维奇教授。这些有机化合物具有BB的大小，但显示了实际的结构和电学性质 人类的大脑。它们由人类细胞制成，显示了细胞类型和电子信息 人类的大脑。初步工作表明，这些迷你大脑可以感染Tau病理，现在 我们的各种候选药物对聚集的Tau的传播和破坏的干扰能力 可以在它们身上进行测试。如果成功，这种方法可以为测试阿尔茨海默氏症药物提供一种新的途径 在人体试验之前。为了进行比较，我们的抑制剂和解聚剂也将在小鼠身上进行评估 直立面疗法模型。