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

微管相关蛋白tau的病理性聚集及其随后积累成神经元缠结（NFT）和其他过度磷酸化的含tau包涵体是阿尔茨海默病（AD）和统称为tau蛋白病的几种其他神经退行性疾病的组织病理学特征。这些疾病影响着美国数百万人，并给受影响的人及其亲人带来巨大的个人和经济损失。然而，虽然脑中的淀粉样蛋白-β（Aβ）和tau聚集体是AD的常见病理学标志，但该疾病是异质的，具有不同的共病病理学和症状进展率。最近的研究表明，NFT不是Tau蛋白病中毒性最大的Tau蛋白实体;相反，Tau寡聚体-单体和NFT之间的可溶性中间体-由于其毒性、接种效力和传播特定异常Tau构象的能力而成为重要的药物靶标，从而引发广泛的Tau病理。我们的数据表明，由不同蛋白质组成的寡聚体可能会引起增加和多样化的tau寡聚化，导致不同的病理和表型，有时与其他神经退行性疾病重叠。tau寡聚体的动态和疏水性质允许形成包括不同tau寡聚体构象异构体（菌株）的聚集体的异质群体。 在本提案中，我们将通过定义菌株特征和菌株形成和传播的潜在机制来测试AD中的tau寡聚菌株假说。具体目标1将检验在AD脑和CSF中发现不同tau寡聚体菌株的假设。具体目标2将检验脑源性tau寡聚体菌株由交叉接种其他淀粉样蛋白产生并在体内传播病理的假设。 这项研究提案将产生有用的结果，具有巨大的潜力，以促进诊断和治疗应用的发展，以靶向AD中的毒性tau寡聚体。阐明不同的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，并确定治疗AD的上游药物靶点。此外，更好地了解tau菌株可以帮助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，并引入个性化药物治疗AD和其他tau蛋白病的令人兴奋的可能性。

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.