Formation and Propagation of Tau Oligomeric Strains in Alzheimer's Disease

阿尔茨海默病中 Tau 寡聚菌株的形成和繁殖

基本信息

批准号：
9903182
负责人：
Rakez Kayed
金额：
$ 38.75万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903182
关键词：
Address Advanced Development Affect Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease brain Amyloid beta-Protein Biochemical Biological Biophysics Brain Cell Culture Techniques Characteristics Clinical Trials Data Development Diagnosis Diagnostic Disease Disease Progression Drug Targeting Evaluation Financial cost Foundations Future Health Heterogeneity Human Hydrophobicity Immunologics Immunotherapeutic agent Incidence Lead Methods Molecular Conformation Monoclonal Antibodies Nature Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Pathologic Pathology Personal Satisfaction Phenotype Play Population Heterogeneity Proteins Research Proposals Role Sampling Seeds Stains Structure Symptoms Tauopathies Testing Therapeutic Tissues Toxic effect United States Wild Type Mouse abeta oligomer aging population biophysical techniques brain tissue comorbidity conformer design drug candidate effective therapy hTau Mice hyperphosphorylated tau improved in vivo innovation insight loved ones monomer new therapeutic target novel novel therapeutics personalized diagnostics personalized medicine personalized therapeutic prion-like protein aggregation screening tau Proteins tau aggregation tau conformation tau mutation uptake

项目摘要

The pathological aggregation of the microtubule-associated protein tau and its subsequent accumulation into neurofibrillary tangles (NFTs) and other hyperphosphorylated tau-containing inclusions are defining histopathological features of Alzheimer’s disease (AD) and several other neurodegenerative disorders collectively known as tauopathies. These diseases affect millions of people in the United States and exact enormous personal and financial costs on those afflicted and their loved ones. However, while amyloid-β (Aβ) and tau aggregates in the brain are the common pathological hallmarks of AD, the disease is heterogeneous with different comorbid pathologies and symptom progression rates. Recent studies suggest that NFTs are not the most toxic tau entities in tauopathies; rather tau oligomers—soluble intermediates between monomers and NFTs—have emerged as an important drug target due to their toxicity, seeding potency, and ability to propagate a specific abnormal tau conformation and thus initiate widespread tau pathology. Our data suggest that oligomers composed of different proteins might give rise to increased and diverse tau oligomerization, resulting in different pathologies and phenotypes that sometimes overlap with other neurodegenerative diseases. The dynamic and hydrophobic nature of tau oligomers allows for the formation of heterogeneous populations of aggregates that include distinct tau oligomeric conformers (strains). In this proposal we will test the tau oligomeric strain hypothesis in AD by defining strain characteristics and potential mechanisms of strain formation and propagation. Specific aim 1 will test the hypothesis that diverse tau oligomeric strains are found in AD brain and CSF. Specific aim 2 will test the hypothesis that brain-derived tau oligomeric strains arise from cross-seeding other amyloidogenic proteins and propagate pathology in vivo. This research proposal will yield useful results with great potential to advance the development of diagnostic and therapeutic applications to target toxic tau oligomers in AD. The elucidation of different tau oligomeric strains and their roles in disease progression may reveal novel therapeutic strategies and identify upstream drug targets for treating AD. Moreover, a better understanding of tau strains could help identify useful approaches for screening the best drug candidates. Finally, it could provide novel insights into the design of future clinical trials and introduce the exciting possibility of personalized medicine to treat AD and other tauopathies.

微管相关蛋白 tau 的病理性聚集及其随后累积成神经原纤维缠结 (NFT) 和其他过度磷酸化的 tau 内含物，定义了阿尔茨海默病 (AD) 和其他几种统称为 tau 病的神经退行性疾病的组织病理学特征。美国有数百万人遭受苦难，他们及其亲人为此付出了巨大的个人和经济代价。 β 淀粉样蛋白 (Aβ) 和 tau 蛋白在大脑中聚集是 AD 的常见病理标志，该疾病具有不同的共病病理和症状进展率，而最近的研究表明，NFT 并不是 tau 蛋白病中毒性最强的 tau 蛋白实体。寡聚物——单体和 NFT 之间的可溶性中间体——由于其毒性、播种效力和传播特定异常的能力，已成为重要的药物靶点我们的数据表明，由不同蛋白质组成的寡聚体可能会导致 tau 寡聚化的增加和多样化，从而导致不同的病理学和表型，有时与其他神经退行性疾病重叠。允许形成异质聚集体群体，其中包括不同的 tau 寡聚构象异构体（菌株）。在本提案中，我们将通过定义菌株特征以及菌株形成和传播的潜在机制来测试 AD 中的 tau 寡聚菌株假设。具体目标 1 将测试在 AD 大脑和脑脊液中发现多种 tau 寡聚菌株的假设。检验以下假设：脑源性 tau 寡聚菌株是由其他淀粉样蛋白交叉播种而产生并在体内传播病理学的。这项研究计划将产生有用的结果，具有巨大的潜力，可推动针对 AD 中有毒 tau 寡聚体的诊断和治疗应用的开发。阐明不同 tau 寡聚体菌株及其在疾病进展中的作用可能会揭示新的治疗策略并确定上游药物靶点。此外，更好地了解 tau 菌株有助于确定筛选最佳候选药物的有用方法，最后，它可以为未来临床试验的设计提供新的见解，并引入个性化医疗治疗 AD 的令人兴奋的可能性。其他tau蛋白病。