Role of Species-Specific Primary Structure Differences in Aβ42 Assembly and Neurotoxicity.
Role of Species-Specific Primary Structure Differences in Aβ42 Assembly and Neurotoxicity.
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DOI：
10.1021/acschemneuro.5b00180
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发表时间：
2015-12-16
影响因子：
5
通讯作者：
Teplow DB
中科院分区：
文献类型：
--
作者：
Roychaudhuri R;Zheng X;Lomakin A;Maiti P;Condron MM;Benedek GB;Bitan G;Bowers MT;Teplow DB
多种物种表达淀粉样β蛋白（Aβ）。已发现那些表达具有与人类中表达的Aβ相同的一级结构的Aβ的物种发展淀粉样蛋白沉积和阿尔茨海默病样神经病理学。相比之下，小鼠和大鼠中的Aβ序列包含三个氨基酸取代，Arg 5Gly，His 13 Arg和Tyr 10 Phe，这显然阻止了AD样神经病理学的发展。有趣的是，刷尾大鼠（学名：Escherdon degus）表达的Aβ仅含有其中一种取代（His 13 Arg），并确实发生了AD样病理。我们在这里调查的生物物理和生物学特性的Aβ肽从人类，小鼠（Mus musculus），和大鼠（Dendon degus）。我们发现，每种肽显示统计卷曲→β折叠二级结构转变;疏水表面的暂时形成;寡聚化;环，原纤维和原纤维的形成;以及聚集速率和聚集体大小之间的负相关性（更快的聚集产生更小的聚集体）。聚集率大小顺序为小鼠>大鼠> Aβ42。制备后即刻各肽形成的组装体的神经毒性大小顺序为Aβ42 >小鼠和大鼠。这些数据不支持长期存在的假设，即控制啮齿动物AD样神经病理学发展的主要因素是Aβ序列。相反，这些数据支持一个假设，即组装四级结构和有机体对毒性肽组装的反应介导神经病理学效应。这一假设的含义是，在给定的系统（生物体，组织等）内对疾病因果关系的有效理解。需要共同评估该系统的生物物理和细胞生物学特性。
A variety of species express the amyloid β-protein (Aβ). Those species expressing Aβ with primary structure identical to that expressed in humans have been found to develop amyloid deposits and Alzheimer’s disease-like neuropathology. In contrast, the Aβ sequence in mice and rats contains three amino acid substitutions, Arg5Gly, His13Arg, and Tyr10Phe, which apparently prevent the development of AD-like neuropathology. Interestingly, the brush-tailed rat, Octodon degus, expresses Aβ containing only one of these substitutions, His13Arg, and does develop AD-like pathology. We investigate here the biophysical and biological properties of Aβ peptides from humans, mice (Mus musculus), and rats (Octodon degus). We find that each peptide displays statistical coil→β-sheet secondary structure transitions; transitory formation of hydrophobic surfaces; oligomerization; formation of annuli, protofibrils, and fibrils; and an inverse correlation between rate of aggregation and aggregate size (faster aggregation produced smaller aggregates). The rank order of assembly rate was mouse > rat > Aβ42. The rank order of neurotoxicity of assemblies formed by each peptide immediately after preparation was Aβ42 > mouse ≈ rat. These data do not support long-standing hypotheses that the primary factor controlling development of AD-like neuropathology in rodents is Aβ sequence. Instead, the data support a hypothesis that assembly quaternary structure and organismal responses to toxic peptide assemblies mediate neuropathogenetic effects. The implication of this hypothesis is that a valid understanding of disease causation within a given system (organism, tissue, etc.) requires the co-evaluation of both biophysical and cell biological properties of that system.