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

微管相关蛋白tau的病理聚集及其随后积聚成神经原纤维缠结（nft）和其他过度磷酸化的含tau的内含物是阿尔茨海默病（AD）和其他几种神经退行性疾病（统称为tau病）的组织病理学特征。这些疾病影响着美国数以百万计的人，并使患者及其亲人付出了巨大的个人和经济代价。然而，尽管大脑中的淀粉样蛋白-β (Aβ)和tau聚集物是AD的常见病理标志，但该疾病具有异质性，具有不同的共病病理和症状进展率。最近的研究表明，nft并不是tau病变中毒性最大的tau实体；相反，tau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低聚物可能引起tau低聚化的增加和多样化，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低聚物的动态和疏水性特性允许形成异质群体的聚集体，包括不同的tau低聚物构象（菌株）。

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.