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N-Terminal Modified Aβ Variants Enable Modulations to the Structures and Cytotoxicity Levels of Wild-Type Aβ Fibrils through Cross-Seeding.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-06-30 , DOI: 10.1021/acschemneuro.0c00316 Zhi-Wen Hu 1 , Dan Fai Au 2 , Letticia Cruceta 1 , Liliya Vugmeyster 2 , Wei Qiang 1
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-06-30 , DOI: 10.1021/acschemneuro.0c00316 Zhi-Wen Hu 1 , Dan Fai Au 2 , Letticia Cruceta 1 , Liliya Vugmeyster 2 , Wei Qiang 1
Affiliation
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Post-translational modifications (PTMs) of β-amyloid (Aβ) peptides are considered as triggering factors in sporadic Alzheimer’s disease. However, studies to show the influence of pre-existing 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 particular 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 a similar chemical nature, such as the S8-phosphorylation and Y10-nitration, both of which 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.
中文翻译：
N末端修饰的Aβ变体能够通过交叉播种调节野生型Aβ原纤维的结构和细胞毒性水平。
β-淀粉样蛋白（Aβ）肽的翻译后修饰（PTM）被认为是偶发性阿尔茨海默氏病的触发因素。然而，很少有研究显示预先存在的PTM-Aβ原纤维对直接模拟触发情况的野生型Aβ肽的影响。在这里，我们显示了三种类型的病理相关PTM-Aβ变体，在一级序列的特定片段（从D7至V12）中有修饰，对野生型Aβ肽的原纤维化产生了不同的影响。通常，通过在PTM-Aβ种子和野生型肽之间进行交叉播种观察到了触发作用，从而导致了所得野生型原纤维结构的调节和原纤维细胞毒性水平的升高。具有相似化学性质的修饰，例如S8-磷酸化和Y10-硝化，它们都引入了额外的侧链负电荷，它们具有可比的结构调节和细胞毒性升高作用。结果暗示PTM-Aβ变体通过交叉播种的原纤维化对淀粉样沉积物形成的生物学影响。
更新日期：2020-07-15
中文翻译：
N末端修饰的Aβ变体能够通过交叉播种调节野生型Aβ原纤维的结构和细胞毒性水平。
β-淀粉样蛋白（Aβ）肽的翻译后修饰（PTM）被认为是偶发性阿尔茨海默氏病的触发因素。然而，很少有研究显示预先存在的PTM-Aβ原纤维对直接模拟触发情况的野生型Aβ肽的影响。在这里，我们显示了三种类型的病理相关PTM-Aβ变体，在一级序列的特定片段（从D7至V12）中有修饰，对野生型Aβ肽的原纤维化产生了不同的影响。通常，通过在PTM-Aβ种子和野生型肽之间进行交叉播种观察到了触发作用，从而导致了所得野生型原纤维结构的调节和原纤维细胞毒性水平的升高。具有相似化学性质的修饰，例如S8-磷酸化和Y10-硝化，它们都引入了额外的侧链负电荷，它们具有可比的结构调节和细胞毒性升高作用。结果暗示PTM-Aβ变体通过交叉播种的原纤维化对淀粉样沉积物形成的生物学影响。
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