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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：
10544785
负责人：
DAVID EISENBERG
金额：
$ 119.25万
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：
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/10544785
关键词：
3-Dimensional Address Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease test American Amyloid beta-Protein Amyloidosis Antibodies Autopsy Brain Cells Collaborations Complex Cryoelectron Microscopy Data Collection Dementia Development Disease Drug Binding Site Drug Design Electron Microscopy Epigallocatechin Gallate Etiology Exhibits Frustration HIV/AIDS 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 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

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. 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.

项目总结