SYNTHETIC PEPTIDE HOMOLOGOUS TO BETA-PROTEIN FROM ALZHEIMER-DISEASE FORMS AMYLOID-LIKE FIBRILS INVITRO
SYNTHETIC PEPTIDE HOMOLOGOUS TO BETA-PROTEIN FROM ALZHEIMER-DISEASE FORMS AMYLOID-LIKE FIBRILS INVITRO
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DOI：
10.1073/pnas.84.19.6953
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发表时间：
1987-10-01
影响因子：
11.1
通讯作者：
SELKOE, DJ
中科院分区：
文献类型：
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作者：
KIRSCHNER, DA;INOUYE, H;SELKOE, DJ
进行性淀粉样蛋白沉积在老年斑和皮质血管中可能在阿尔茨海默病的发病机制中发挥核心作用。我们用X射线衍射仪和电子显微镜研究了三个与β-β同源的合成肽形成的大分子集合体的分子结构和形态。脑淀粉样蛋白：β-(1-28)，β残基1-28。蛋白质；[Ala16]β-(1-28)，β-(1-28)，丙氨酸取代16位赖氨酸；和β-(18-28)，β残基18-28。蛋白。β-(1-28)在体外容易形成类似于体内淀粉样蛋白的超微结构的纤维，并聚集成类似于衰老斑块核心的大束。部分干燥的定向颗粒的X射线图谱显示为交叉β构象。一系列小角度的赤道最大值与平均直径为86°的管状原纤维和由一对交叉-β-褶皱的薄片组成的壁相一致。该数据也可以与居中分开71-ANG的成对交叉β-薄片相一致。[Ala16]β-(1-28)形成不同于体内纤维的β-褶皱片状组件。10角间隔的宽度表示大约六张纸的堆叠。因此，β-链区域中带正电的赖氨酸被不带电荷的丙氨酸取代，增强了片层的堆积，并极大地改变了形成的大分子聚集体的类型。β-(18-28)形成的组件具有更多的堆叠的片层，并且每个衍射域有24个，由尖锐的片间反射所指示。我们在这些同源合成组件上的发现有助于定义形成阿尔茨海默型淀粉样纤维所需的特定序列，从而提供了一个与年龄相关的脑淀粉样蛋白发生的体外模型。
Progressive amyloid deposition in senile plaques and cortical blood vessels may play a central role in the pathogenesis of Alzheimer disease. We have used x-ray diffraction and electron microscopy to study the molecular organization and morphology of macromolecular assemblies formed by three synthetic peptides homologous to .beta. protein of brain amyloid: .beta.-(1-28), residues 1-28 of the .beta. protein; [Ala16].beta.-(1-28), .beta.-(1-28) with alanine substituted for lysine at position 16; and .beta.-(18-28), residues 18-28 of the .beta. protein. .beta.-(1-28) readily formed fibrils in vitro that were similar in ultrastructure to the in vivo amyloid and aggregated into large bundles resembling those of senile plaque cores. X-ray patterns from partially dried, oriented pellets showed a cross-.beta.-conformation. A series of small-angle, equatorial maxima were consistent with a tubular fibril having a mean diameter of 86 .ANG. and a wall composed of pairs of cross-.beta.-pleated sheets. The data may also be consistent with pairs of cross-.beta.-sheets that are centered 71-.ANG. apart. [Ala16].beta.-(1-28) formed .beta.-pleated sheet assemblies that were dissimilar to in vivo fibrils. The width of the 10-.ANG. spacing indicated stacks of about six sheets. Thus, substitution of the uncharged alanine for the positively charged lysine in the .beta.-strand region enhances the packing of the sheets and dramatically alters the type of macromolecular aggregate formed. .beta.-(18-28) formed assemblies that had even a greater number of stacked sheets, and 24 per diffracting domain as indicated by the sharp intersheet reflection. Our findings on these homologous synthetic assemblies help to define the specific sequence that is required to form Alzheimer-type amyloid fibrils, thus providing an in vitro model of age-related cerebral amyloidogenesis.