N-Terminal Modified Aβ Variants Enable Modulations to the Structures and Cytotoxicity Levels of Wild-Type Aβ Fibrils through Cross-Seeding.
N-Terminal Modified Aβ Variants Enable Modulations to the Structures and Cytotoxicity Levels of Wild-Type Aβ Fibrils through Cross-Seeding.
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DOI：
10.1021/acschemneuro.0c00316
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发表时间：
2020-07-15
影响因子：
5
通讯作者：
Qiang W
中科院分区：
文献类型：
--
作者：
Hu ZW;Au DF;Cruceta L;Vugmeyster L;Qiang W
β-淀粉样蛋白(Aβ)多肽的翻译后修饰(PTM)被认为是散发性阿尔茨海默病的触发因素。然而，关于预先存在的pTm-Aβ纤维对直接模拟触发场景的野生型Aβ多肽的影响的研究很少。在这里，我们证明了三种类型的病理相关的Ptm-Aβ变体，在初级序列的相似片段(从D7到V12)上进行修改，导致对野生型Aβ多肽的纤化产生不同的影响。一般来说，触发效应是通过在Ptm-Aβ种子和野生型多肽之间交叉播种观察到的，从而诱导对所产生的野生型纤维结构的调制和纤维细胞毒性水平的升高。具有相似化学性质的修饰，如S8-磷酸化和Y10-硝化，都引入了额外的侧链负电荷，显示出类似的结构调节和细胞毒性提高的效果。这些结果暗示了pTm-Aβ变异体通过交叉种子纤化作用对淀粉样蛋白沉积形成的生物学影响。
Post-translational modifications (PTMs) of β-amyloid (Aβ) peptides are considered as triggering factors in sporadic Alzheimer’s diseases. However, studies to show the influences of pre-existed PTM-Aβ fibrils on wild-type Aβ peptides, which directly mimic the triggering scenarios, are rare. Here we show that three types of pathologically relevant PTM-Aβ variants with modifications in a similar segment (from D7 to V12) of the primary sequence lead to distinct impacts on the fibrillization of wild-type Aβ peptides. In general, the triggering effects are observed through cross-seeding between the PTM-Aβ seeds and wild-type peptides, which consequently induce modulations in the resultant wild-type fibril structures and elevations in the fibrillar cytotoxicity levels. Modifications with the similar chemical nature, such as the S8-phosphorylation and Y10-nitration, which both introduce additional side-chain negative charges, show comparable structural-modulation and cytotoxicity-elevation effects. The results imply the biological influences of PTM-Aβ variants on the formation of amyloid deposits through cross-seeded fibrillization.
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影响因子：
1.2
作者：
Barykin, E. P.;Petrushanko, I. Yu.;Mitkevich, V. A.
通讯作者：
Mitkevich, V. A.
影响因子：
15
作者：
Colvin MT;Silvers R;Frohm B;Su Y;Linse S;Griffin RG
通讯作者：
Griffin RG
影响因子：
64.8
作者：
Qiang W;Yau WM;Lu JX;Collinge J;Tycko R
通讯作者：
Tycko R
DOI：
10.1186/alzrt258
发表时间：
2014
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Kummer MP;Heneka MT
通讯作者：
Heneka MT
影响因子：
15
作者：
Qiang, Wei;Yau, Wai-Ming;Tycko, Robert
通讯作者：
Tycko, Robert