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聚集成神经纤维缠结(NFTs)和其他含有tau的过度磷酸化的包涵体定义了阿尔茨海默病(AD)和其他几种神经退行性疾病的组织病理学特征，统称为tauopathies。这些疾病影响着美国数以百万计的人，给患者及其亲人带来巨大的个人和经济损失。然而，虽然大脑中的淀粉样蛋白(Aβ，Aβ)和tau聚集体是AD的共同病理特征，但该疾病具有不同的共病病理和症状进展率。最近的研究表明，在tau病中，nft不是毒性最强的tau实体；相反，tau寡聚体--单体和nft之间的可溶中间体--由于其毒性、种子效力和繁殖特定异常tau构象的能力而成为重要的药物靶点，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更多和不同的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(菌株)的聚集体的异质群体。 在这项建议中，我们将通过定义菌株特征和菌株形成和繁殖的潜在机制来检验tau寡聚菌株在AD中的假说。特定目标1将测试在AD脑和脑脊液中发现不同tau寡聚体菌株的假设。《特定目标2》将验证脑源性tau寡聚体菌株来自于交叉播种其他淀粉样蛋白并在体内传播病理的假说。 这项研究提案将产生有用的结果，具有极大的潜力推动针对AD中毒性tau寡聚体的诊断和治疗应用的发展。阐明不同的tau寡聚体菌株及其在疾病进展中的作用可能揭示新的治疗策略，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阿尔茨海默病和其他疾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.