Structural variation in amyloid-β fibrils from Alzheimer's disease clinical subtypes.
Structural variation in amyloid-β fibrils from Alzheimer's disease clinical subtypes.
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DOI：
10.1038/nature20814
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发表时间：
2017-01-12
期刊：
影响因子：
64.8
通讯作者：
Tycko R
中科院分区：
文献类型：
--
作者：
Qiang W;Yau WM;Lu JX;Collinge J;Tycko R
淀粉样蛋白-β (Aβ)肽聚集成原纤维或其他自组装状态是阿尔茨海默病（AD）发病机制的核心。在体外，由40-和42-残基Aβ肽（a - β40和a - β42）形成的原纤维具有多态性，其分子结构的变化取决于原纤维的生长条件。最近的实验表明，体内Aβ纤维结构的变化可能与AD表型的变化相关，就像不同的朊病毒株与不同的临床和病理表型相关一样。本研究利用固态核磁共振（ssNMR）技术对AD大脑皮层提取物种子生长制备的Aβ40和Aβ42原纤维进行了结构变异与AD表型之间的相关性研究。我们比较了两种非典型阿尔茨海默病临床亚型，快速进行性阿尔茨海默病（r-AD）和后皮质萎缩变型阿尔茨海默病（PCA-AD），以及典型的持续时间较长的阿尔茨海默病（t-AD）。基于来自18个个体的37个皮质组织样本的ssmr数据，我们发现t-AD和PCA-AD患者样本中单个a β40原纤维结构最为丰富，而r-AD样本中的a β40原纤维显示出更大比例的附加结构。Aβ42原纤维的数据表明，在所有患者类别的大多数样本中，Aβ42原纤维的结构存在异质性，至少存在两种普遍结构。这些结果表明，在t-AD和PCA-AD中存在一种特殊的显性a β40纤维结构，表明r-AD可能与额外的纤维结构有关，并表明AD脑组织中a β40和a β42聚集物存在质的差异。
Aggregation of amyloid-β (Aβ) peptides into fibrils or other self-assembled states is central to Alzheimer’s disease (AD) pathogenesis. Fibrils formed in vitro by 40- and 42-residue Aβ peptides (Aβ40 and Aβ42) are polymorphic, with variations in molecular structure that depend on fibril growth conditions. Recent experiments suggest that variations in Aβ fibril structure in vivo may correlate with variations in AD phenotype, in analogy to distinct prion strains that are associated with distinct clinical and pathological phenotypes. Here we have investigated correlations between structural variation and AD phenotype using solid state nuclear magnetic resonance (ssNMR) measurements on Aβ40 and Aβ42 fibrils prepared by seeded growth from extracts of AD brain cortex. We compared two atypical AD clinical subtypes, rapidly progressive AD (r-AD) and the posterior cortical atrophy variant (PCA-AD), with typical prolonged duration AD (t-AD). Based on ssNMR data from 37 cortical tissue samples from 18 individuals, we find that a single Aβ40 fibril structure is most abundant in samples from t-AD and PCA-AD patients, while Aβ40 fibrils from r-AD samples exhibit a significantly greater proportion of additional structures. Data for Aβ42 fibrils indicate structural heterogeneity in most samples from all patient categories, with at least two prevalent structures. These results demonstrate the existence of a specific predominant Aβ40 fibril structure in t-AD and PCA-AD, suggest that r-AD may relate to additional fibril structures, and suggest a qualitative difference between Aβ40 and Aβ42 aggregates in AD brain tissue.