Sterol-activated amyloid beta fibril formation.
Sterol-activated amyloid beta fibril formation.
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DOI：
10.1016/j.jbc.2023.105445
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发表时间：
2023-12
影响因子：
4.8
通讯作者：
Leyh, Thomas S.
中科院分区：
文献类型：
--
作者：
Cook, Ian;Leyh, Thomas S.
将阿尔茨海默病（AD）与大脑中胆固醇水平升高联系起来的代谢过程尚未完全确定。β淀粉样蛋白（Aβ）斑块积聚被认为在症状出现前开始数十年就已开始，并对疾病有显著影响。胆固醇及其代谢产物通过尚未明确的机制加速斑块形成。在此，通过定量配体结合、Aβ42纤维聚合和分子动力学研究，对胆固醇（CH）和胆固醇3-硫酸盐（CS）诱导加速Aβ42纤维形成的机制进行了研究。平衡和预稳态结合研究表明，单体Aβ42·配体复合物相对于寡聚化快速形成和解离，配体/肽的化学计量比为1：1，并且肽在体内可能饱和。Aβ42聚合进程曲线的分析表明，配体通过催化肽单体转化为二聚体来加速聚合物合成，二聚体使聚合反应成核。成核被CH加速了49倍，被CS加速了13，000倍，CS是一种次要的CH代谢物。聚合动力学模型预测，在假定的疾病相关CS和CH浓度下，大约一半的聚合核将含有CS，神经毒性尺寸的小寡聚体（12-mer）将含有大量CS，原纤维形成滞后时间将相对于未配体的Aβ42减少13倍。分子动力学模型，定量预测所有的实验结果，表明加速机制是植根于配体诱导的稳定的肽在非螺旋构象，容易形成聚合核。
The metabolic processes that link Alzheimer’s disease (AD) to elevated cholesterol levels in the brain are not fully defined. Amyloid beta (Aβ) plaque accumulation is believed to begin decades prior to symptoms and to contribute significantly to the disease. Cholesterol and its metabolites accelerate plaque formation through as-yet-undefined mechanisms. Here, the mechanism of cholesterol (CH) and cholesterol 3-sulfate (CS) induced acceleration of Aβ42 fibril formation is examined in quantitative ligand binding, Aβ42 fibril polymerization, and molecular dynamics studies. Equilibrium and pre-steady-state binding studies reveal that monomeric Aβ42•ligand complexes form and dissociate rapidly relative to oligomerization, that the ligand/peptide stoichiometry is 1-to-1, and that the peptide is likely saturated in vivo. Analysis of Aβ42 polymerization progress curves demonstrates that ligands accelerate polymer synthesis by catalyzing the conversion of peptide monomers into dimers that nucleate the polymerization reaction. Nucleation is accelerated ∼49-fold by CH, and ∼13,000-fold by CS — a minor CH metabolite. Polymerization kinetic models predict that at presumed disease-relevant CS and CH concentrations, approximately half of the polymerization nuclei will contain CS, small oligomers of neurotoxic dimensions (∼12-mers) will contain substantial CS, and fibril-formation lag times will decrease 13-fold relative to unliganded Aβ42. Molecular dynamics models, which quantitatively predict all experimental findings, indicate that the acceleration mechanism is rooted in ligand-induced stabilization of the peptide in non-helical conformations that readily form polymerization nuclei.
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DOI：
10.1021/acs.jpcb.5b09557
发表时间：
2016-01-14
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Elbassal EA;Liu H;Morris C;Wojcikiewicz EP;Du D
通讯作者：
Du D
DOI：
10.1016/j.bbapap.2010.04.001
发表时间：
2010-07
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Biancalana M;Koide S
通讯作者：
Koide S
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
DOI：
10.1074/jbc.ra120.015177
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Cook I;Cacace M;Wang T;Darrah K;Deiters A;Leyh TS
通讯作者：
Leyh TS
影响因子：
6.1
作者：
Evangelopoulos, Maria-Eleftheria;Koutsis, Georgios;Markianos, Manolis
通讯作者：
Markianos, Manolis