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的 神经纤维缠结（NFT）的沉积是阿尔茨海默病的组织病理学特征 疾病（AD）和许多其他神经退行性疾病。虽然积累的tau蛋白 大脑中的聚集物是AD的一贯标志，在进展中存在大量的聚集物。 发病率和症状多样性。大量证据表明，AD 与朊病毒疾病在蛋白质聚集方面具有重要特征， tau和Aβ的构象变体可以在细胞模型中诱导聚集的模板化， vivo.最近的进展引发了一系列关键问题，如i）变量tau如何聚集 菌株可以是，ii）形成具有在脑区域内扩散的能力的tau菌株，和 诱导天然tau的聚集，iii）不同tau株先于和 伴随其他淀粉样蛋白聚集。 我们的中心假设是，AD相关tau寡聚体菌株的生物学特性与AD相关性相关。 特定的遗传背景和混合蛋白质病理学编码在这些结构中， 集料.因此，不同的tau寡聚体菌株之间的相互作用/竞争是关键的。 控制疾病进展程度和引发明确毒性的决定因素 AD中的级联。鉴定最主要的和潜伏的菌株对于 通过增强对毒性药物的准确靶向来设计个性化治疗策略 物种 该提案基于我们的出色进展和令人兴奋的初步数据，并得到了以下方面的支持： 我们有能力的团队和合作者，将解决tau寡聚菌株生物学和 在寡聚体染色中占优势的未探索的作用，从而调节疾病进展， AD表型，当代NIH最相关的任务使命领域之一。新的见解 从这项研究中获得的信息将导致未来临床试验的设计和 个性化医疗

The pathological aggregation of the microtubule-associated protein tau and its subsequent deposition in neurofibrillary tangles (NFTs) are defining histopathological features of Alzheimer’s disease (AD) and many other neurodegenerative disorders. Although accumulated tau protein aggregates in the brain are a consistent hallmark of AD, there is a vast array in the progression rate of disease and diversity in symptoms. An expansive body of evidence demonstrates that AD shares important characteristics with prion diseases in terms of protein aggregation where conformational variants of tau and Aβ can induce templating of aggregation in cell models or in vivo. Recent advances have spurred a series of critical questions as i) how variable tau aggregate strains can be, ii) formation of tau strains with the ability of spreading within the brain regions and induce aggregation of native tau, iii) the propensity of diverse tau strains to precede and accompany other amyloid aggregation. Our central hypothesis is that the biological properties of AD-relevant tau oligomer strains in specific genetic background and mixed protein pathologies are encoded in the structure of these aggregates. Thus, the interplay/competition between distinct tau oligomer strains is a critical determinant in controlling the extent of disease progression and initiating definite toxicity cascades in AD. The identification of the most dominant and latent strains will be crucial for the design of personalized therapeutic strategies by enhancing accurate targeting of the toxic species. This proposal is based on our excellent progress and exciting preliminary data and supported by our competent team and collaborators, will address tau oligomeric strain biology and the unexplored role of domination in oligomer stains, thus regulating disease progression and phenotypes in AD, one of the most relevant contemporary NIH mission areas. The novel insights gained from this study will lead to the future designing of clinical trials and the possibility for personalized medicine.