Pyroglutamylated amyloid-β peptide reverses cross β-sheets by a prion-like mechanism.
Pyroglutamylated amyloid-β peptide reverses cross β-sheets by a prion-like mechanism.
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DOI：
10.1021/jp412743s
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发表时间：
2014-05-29
期刊：
影响因子：
--
通讯作者：
Tatulian SA
中科院分区：
文献类型：
--
作者：
Matos JO;Goldblatt G;Jeon J;Chen B;Tatulian SA
淀粉样蛋白假说认为淀粉样β肽（A β）的纤维状沉积与阿尔茨海默病（AD）有因果关系。然而，最近的数据确定可溶性低聚物为主要的细胞毒性实体。焦谷氨酰化A β（pE-A β）存在于AD脑中并发挥增强的神经毒性，这被认为是由于其更高的β-折叠倾向和更快的纤维化。虽然这一概念是基于一组实验结果，但其他人已经报道了未修饰和焦谷氨酰化A β中的β-折叠含量相似，并且与未修饰A β相比，pE-A β的聚集较慢，使得问题未得到解决。在这里，我们评估了A β和pE-A β肽之间的结构差异，这些差异可能是其不同细胞毒性的基础。透射电子显微镜在聚集的早期阶段鉴定了大量的pE-A β的前原纤维聚集体，并表明即使在低摩尔分数下，pE-A β也会影响原纤维形成。圆二色性和FTIR数据表明，虽然未修饰的A β在水性介质中容易形成β-折叠原纤维，但pE-A β显示出增加的α-螺旋和减少的β-折叠倾向。此外，同位素编辑的FTIR光谱显示，pE-A β通过朊病毒样机制逆转β-折叠形成，从而逆转未修饰的A β肽的原纤维形成。这些数据为pE-A β高毒性提供了一种新的结构机制;由于其疏水性增加，pE-A β经历了更快的前原纤维聚集体形成，从而将原纤维形成的初始阶段转移到部分α-螺旋结构的更小的高毒性寡聚体。
The amyloid hypothesis causatively relates the fibrillar deposits of amyloid β peptide (Aβ) to Alzheimer’s disease (AD). More recent data, however, identify the soluble oligomers as the major cytotoxic entities. Pyroglutamylated Aβ (pE-Aβ) is present in AD brains and exerts augmented neurotoxicity, which is believed to result from its higher β-sheet propensity and faster fibrillization. While this concept is based on a set of experimental results, others have reported similar β-sheet contents in unmodified and pyroglutamylated Aβ, and slower aggregation of pE-Aβ as compared to unmodified Aβ, leaving the issue unresolved. Here, we assess the structural differences between Aβ and pE-Aβ peptides that may underlie their distinct cytotoxicities. Transmission electron microscopy identifies a larger number of prefibrillar aggregates of pE-Aβ at early stages of aggregation and suggests that pE-Aβ affects the fibrillogenesis even at low molar fractions. Circular dichroism and FTIR data indicate that while the unmodified Aβ readily forms β-sheet fibrils in aqueous media, pE-Aβ displays increased α-helical and decreased β-sheet propensity. Moreover, isotope-edited FTIR spectroscopy shows that pE-Aβ reverses β-sheet formation and hence fibrillogenesis of the unmodified Aβ peptide via a prion-like mechanism. These data provide a novel structural mechanism for pE-Aβ hypertoxicity; pE-Aβ undergoes faster formation of prefibrillar aggregates due to its increased hydrophobicity, thus shifting the initial stages of fibrillogenesis toward smaller, hypertoxic oligomers of partial α-helical structure.
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DOI：
10.1007/978-1-62703-673-3_17
发表时间：
2014-01-01
期刊：
THERAPEUTIC PEPTIDES: METHODS AND PROTOCOLS
影响因子：
--
作者：
Bakshi, Kunal;Liyanage, Mangala R.;Middaugh, C. Russell
通讯作者：
Middaugh, C. Russell
影响因子：
2.9
作者：
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通讯作者：
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DOI：
10.1093/protein/11.9.761
发表时间：
1998-09-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
Chaney, MO;Webster, SD;Roher, AE
通讯作者：
Roher, AE
影响因子：
5.6
作者：
Jeong, Jae Sun;Ansaloni, Annalisa;Dietler, Giovanni
通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
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