Effect of Cholesterol on Membrane Fluidity and Association of Aβ Oligomers and Subsequent Neuronal Damage: A Double-Edged Sword.
Effect of Cholesterol on Membrane Fluidity and Association of Aβ Oligomers and Subsequent Neuronal Damage: A Double-Edged Sword.
复制标题
DOI：
10.3389/fnagi.2018.00226
复制
发表时间：
2018
影响因子：
4.8
通讯作者：
Aguayo LG
中科院分区：
文献类型：
--
作者：
Fernández-Pérez EJ;Sepúlveda FJ;Peters C;Bascuñán D;Riffo-Lepe NO;González-Sanmiguel J;Sánchez SA;Peoples RW;Vicente B;Aguayo LG
背景：参与阿尔茨海默病（AD）的β -淀粉样肽（Aβ）已被描述为在细胞表面结合/聚集，通过孔隙形成和破裂破坏膜。然而，参与这种相互作用的分子决定因素（例如，细胞膜的一些物理化学性质）在很大程度上是未知的。由于胆固醇是膜结构和流动性的重要分子，我们在培养的海马神经元中检测了不同胆固醇含量与Aβ的关联和膜穿孔的影响。方法：分别用甲基β-环糊精（m -β- cd）和m -β cd /胆固醇来降低或提高膜内胆固醇水平。我们利用广义偏振成像（GP）和荧光染料di-4-ANEPPDHQ分析了膜的流动性是否受到影响。此外，分别使用免疫细胞化学和电生理技术评估膜关联和穿孔。结果：胆固醇去除降低了a β与神经元膜的宏观结合（荧光点/20 μm：对照组= 18±2,MβCD = 10±1,p < 0.05），诱导了a β相对于对照细胞的膜穿孔（最大电荷转移的半时间：对照组= 7.2,MβCD = 4.4）。在这种情况下，我们发现膜流动性增加（GP值降低46±3.3%,p < 0.001）。相反，胆固醇水平升高使细胞膜硬度增加（GP值增加38±2.7%,p < 0.001），增强了Aβ的关联和聚集（荧光点/20 μm：对照= 18±2 vs. MβCD = 10±1,p < 0.01），但抑制了膜的破坏。结论：我们的研究结果有力地支持了Aβ在海马神经元毒性作用中质膜组织的重要性，因为流动性可以调节Aβ肽在神经元膜中的分布和插入。
Background: The beta-amyloid peptide (Aβ) involved in Alzheimer’s disease (AD) has been described to associate/aggregate on the cell surface disrupting the membrane through pore formation and breakage. However, molecular determinants involved for this interaction (e.g., some physicochemical properties of the cell membrane) are largely unknown. Since cholesterol is an important molecule for membrane structure and fluidity, we examined the effect of varying cholesterol content with the association and membrane perforation by Aβ in cultured hippocampal neurons. Methods: To decrease or increase the levels of cholesterol in the membrane we used methyl-β-cyclodextrin (MβCD) and MβCD/cholesterol, respectively. We analyzed if membrane fluidity was affected using generalized polarization (GP) imaging and the fluorescent dye di-4-ANEPPDHQ. Additionally membrane association and perforation was assessed using immunocytochemistry and electrophysiological techniques, respectively. Results: The results showed that cholesterol removal decreased the macroscopic association of Aβ to neuronal membranes (fluorescent-puncta/20 μm: control = 18 ± 2 vs. MβCD = 10 ± 1, p < 0.05) and induced a facilitation of the membrane perforation by Aβ with respect to control cells (half-time for maximal charge transferred: control = 7.2 vs. MβCD = 4.4). Under this condition, we found an increase in membrane fluidity (46 ± 3.3% decrease in GP value, p < 0.001). On the contrary, increasing cholesterol levels incremented membrane rigidity (38 ± 2.7% increase in GP value, p < 0.001) and enhanced the association and clustering of Aβ (fluorescent-puncta/20 μm: control = 18 ± 2 vs. MβCD = 10 ± 1, p < 0.01), but inhibited membrane disruption. Conclusion: Our results strongly support the significance of plasma membrane organization in the toxic effects of Aβ in hippocampal neurons, since fluidity can regulate distribution and insertion of the Aβ peptide in the neuronal membrane.
登录
查看更多内容
影响因子：
5.3
作者：
Cecchi C;Rosati F;Pensalfini A;Formigli L;Nosi D;Liguri G;Dichiara F;Morello M;Danza G;Pieraccini G;Peri A;Serio M;Stefani M
通讯作者：
Stefani M
影响因子：
14.5
作者：
Djelti, Fathia;Braudeau, Jerome;Cartier, Nathalie
通讯作者：
Cartier, Nathalie
DOI：
10.1016/j.bbadis.2017.08.013
发表时间：
2017-12-01
影响因子：
6.2
作者：
Fernandez-Perez, E. J.;Sepulveda, F. J.;Aguayo, L. G.
通讯作者：
Aguayo, L. G.
影响因子：
0.700
作者：
I. S. Savanov
通讯作者：
I. S. Savanov
影响因子：
3.7
作者：
Jaureguiberry, Maria S.;Alejandra Tricerri, M.;Rimoldi, Omar J.
通讯作者：
Rimoldi, Omar J.