Alzheimer's Aβ42 and Aβ40 form mixed oligomers with direct molecular interactions.
Alzheimer's Aβ42 and Aβ40 form mixed oligomers with direct molecular interactions.
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DOI：
10.1016/j.bbrc.2020.11.092
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发表时间：
2021-01-01
影响因子：
3.1
通讯作者：
Guo Z
中科院分区：
文献类型：
--
作者：
Gu L;Guo Z
a β低聚物和原纤维的形成在阿尔茨海默病的发病机制中起着核心作用。Aβ在大脑中有两种主要形式：Aβ42和Aβ40。Aβ42是淀粉样斑块的主要成分，但Aβ40的总体丰度是Aβ42的数倍。体外实验表明，a - β42和a - β40相互影响聚集。在阿尔茨海默病小鼠模型中，Aβ40的过度表达已被证明可以减少斑块病理，这表明Aβ42和Aβ40在体内也相互作用。本文利用电子顺磁共振（EPR）光谱分析了Aβ42和Aβ40在低聚物形成过程中是否相互作用。当仅使用自旋标记的Aβ42形成低聚物时，在20 Å范围内的自旋标记之间的偶极相互作用使EPR谱变宽，幅度减小。自旋标记的a β42和野生型a β42混合形成的低聚物由于自旋-自旋相互作用减弱，EPR谱的振幅更高，表明标记的a β42和野生型a β42存在分子混合。当自旋标记的Aβ42与野生型Aβ40混合形成低聚物时，EPR谱的振幅也减小，表明野生型Aβ40也可以与自旋标记的Aβ42形成低聚物。因此，我们的研究结果表明，a - β42和a - β40形成了直接分子相互作用的混合低聚物。我们的研究结果指出了研究a - β42- a - β40在大脑中的相互作用对于全面了解阿尔茨海默病的发病机制和治疗干预的重要性。
Formation of Aβ oligomers and fibrils plays a central role in the pathogenesis of Alzheimer’s disease. There are two major forms of Aβ in the brain: Aβ42 and Aβ40. Aβ42 is the major component of the amyloid plaques, but the overall abundance of Aβ40 is several times that of Aβ42. In vitro experiments show that Aβ42 and Aβ40 affect each other’s aggregation. In mouse models of Alzheimer’s disease, overexpression of Aβ40 has been shown to reduce the plaque pathology, suggesting that Aβ42 and Aβ40 also interact in vivo. Here we address the question of whether Aβ42 and Aβ40 interact with each other in the formation of oligomers using electron paramagnetic resonance (EPR) spectroscopy. When the Aβ42 oligomers were formed using only spin-labeled Aβ42, the dipolar interaction between spin labels that are within 20 Å range broadened the EPR spectrum and reduced its amplitude. Oligomers formed with a mixture of spin-labeled Aβ42 and wild-type Aβ42 gave an EPR spectrum with higher amplitude due to weakened spin-spin interactions, suggesting molecular mixing of labeled and wild-type Aβ42. When spin-labeled Aβ42 and wild-type Aβ40 were mixed to form oligomers, the resulting EPR spectrum also showed reduced amplitude, suggesting that wild-type Aβ40 can also form oligomers with spin-labeled Aβ42. Therefore, our results suggest that Aβ42 and Aβ40 form mixed oligomers with direct molecular interactions. Our results point to the importance of investigating Aβ42-Aβ40 interactions in the brain for a complete understanding of Alzheimer’s pathogenesis and therapeutic interventions.
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DOI：
10.3233/jad-179941
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Cline EN;Bicca MA;Viola KL;Klein WL
通讯作者：
Klein WL
影响因子：
14.5
作者：
Brinkmalm, Gunnar;Hong, Wei;Walsh, Dominic M.
通讯作者：
Walsh, Dominic M.
影响因子：
--
作者：
Mehta, PD;Pirttilä, T;Wisniewski, HM
通讯作者：
Wisniewski, HM
DOI：
10.1073/pnas.95.11.6448
发表时间：
1998-05-26
影响因子：
11.1
作者：
Lambert, MP;Barlow, AK;Klein, WL
通讯作者：
Klein, WL
影响因子：
4.8
作者：
Pauwels, Kris;Williams, Thomas L.;Broersen, Kerensa
通讯作者：
Broersen, Kerensa