Structural determinants of amyloid strain heterogeneity in distinct phenotypes of Alzheimer's disease

聚集的β淀粉样蛋白（Aβ）和过度磷酸化的tau蛋白的沉积与 在散发性和家族性阿尔茨海默病中， 疾病（AD）。这项研究的长期目标是确定负责 AD的不同表型和进展率，并探讨Aβ结构多态性的作用 和tau聚集体作为疾病表型变异性的潜在决定因素。为此我们 提出一个综合的多学科方法，涉及三名主要调查员， 专业知识我们的主要具体目标是描绘AD表型依赖的结构组织 建立结构/功能关系，并确定 控制Aβ淀粉样纤维和tau纤维的朊病毒样菌株的独特致病潜力。大脑中 从表型不同的散发性和家族性AD病例的组织中，我们将进行Aβ的菌株分型， 使用在朊病毒研究中开发和验证的方法来研究tau聚集体。此外，我们将 表征脑源性Aβ和tau聚集体之间的整体结构差异， 不同的AD表型，并评估其播种（复制） 效力，与疾病进展速度相关的体外属性。最后，我们将获得高- 对体外生成的脑源性Aβ和tau的高保真复制品的结构的分辨率洞察 使用固态NMR光谱法，将对应于AD的不同表型的细丝进行比较。建立 Aβ和tau菌株的特定结构特征之间的关系应该揭示 不同形式的AD的发病机制，导致认知能力快速下降的关键因素， AD的重要子集，并检验朊病毒样菌株负责表型 多样性和进步率。这一认识对于开发预测癌症的分子标记物至关重要。 AD的进展和表型，并最终用于新的治疗策略。

The deposition of aggregated amyloid beta (Aβ) and hyperphosphorylated tau proteins is directly associated with cell death and propagation of brain pathology in sporadic as well as familial forms of Alzheimer's disease (AD). The long-term objective of this research is to define the molecular mechanism responsible for diverse phenotypes and progression rates in AD, and to explore the role of structural polymorphism of Aβ and tau aggregates as a potential determinant of phenotypic variability of the disease. To this end, we propose an integrated multidisciplinary approach involving three principal investigators with complementary expertise. Our key specific objectives are to delineate the AD phenotype-dependent structural organization of Aβ and tau aggregates, establish structure/function relationship, and identify key structural attributes that control distinct pathogenic potential of prion-like strains of Aβ amyloid fibrils and tau filaments. In the brain tissue from phenotypically distinct cases of sporadic and familial AD, we will perform strain-typing of Aβ and tau aggregates using approaches that were developed and validated in prion research. Furthermore, we will characterize the overall structural differences between brain-derived Aβ and tau aggregates corresponding to different AD phenotypes using mass spectrometry-based methods and assess their seeding (replication) potency, an in vitro attribute that relates to the progression rate of disease. Finally, we will obtain high- resolution insight into the structure of in vitro generated high-fidelity replicas of brain-derived Aβ and tau filaments corresponding to distinct phenotypes of AD using solid-state NMR spectroscopy. Establishing the relationship between specific structural features of Aβ and tau strains should uncover critical aspects of the pathogenesis in distinct forms of AD, key factors responsible for very rapid rate of cognitive decline in significant subset of AD, and test the hypothesis that prion-like strains are responsible for phenotypic diversity and progression rate. This insight is critical for efforts to develop molecular markers that predict progression and phenotype of AD and ultimately for novel therapeutic strategies.