Role of membrane GM1 on early neuronal membrane actions of Aβ during onset of Alzheimer's disease
Role of membrane GM1 on early neuronal membrane actions of Aβ during onset of Alzheimer's disease
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DOI：
10.1016/j.bbadis.2017.08.013
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发表时间：
2017-12-01
影响因子：
6.2
通讯作者：
Aguayo, L. G.
中科院分区：
文献类型：
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作者：
Fernandez-Perez, E. J.;Sepulveda, F. J.;Aguayo, L. G.
先前已经描述了β-淀粉样肽（A β）通过形成孔和膜破裂来破坏质膜的能力。然而，这些影响的分子决定因素在很大程度上是未知的。在这项研究中，我们研究了是否协会和随后的膜穿孔诱导的所有依赖于GM 1水平。用DPPH预处理海马神经元可减少GM 1和A β在膜上的聚集（A β荧光点/20 μ m，对照组= 16.2 +/- 1.1，DPPH = 6.4 +/- 0.4，p < 0.001）。有趣的是，当GM 1含量减少时，A β的膜穿孔以较慢的时间过程发生（建立穿孔构型的时间（TEPC）（min）：对照= 7.8 +/-2 vs.低GM 1 = 12.1 +/-0.5，p < 0.01），表明膜中GM 1的存在可以调节A β的分布和膜穿孔。另一方面，增加GM 1促进膜穿孔（TEPC：对照= 7.8 +/- 2 vs. GM 1 = 6.2 +/- 1 min，p < 0.05）。此外，使用霍乱毒素亚基-B（CTB）阻断A β与GM 1的相互作用显著减弱膜穿孔。此外，用CTB预处理降低了AD的膜结合（荧光点/20 μ m，A β：对照= 14.8 +/- 2.5 vs. CTB = 8 +/- 1.4，p < 0.05），表明GM 1也在A β与膜的结合和穿孔中起作用。此外，阻断AD与CTB的关联可抑制突触毒性。两者合计，我们的结果强烈表明，膜脂质组合物可以影响A β的能力，以关联，并随后使质膜，从而调节其在海马神经元的神经毒性。
The ability of beta-amyloid peptide (A beta) to disrupt the plasma membrane through formation of pores and membrane breakage has been previously described. However, the molecular determinants for these effects are largely unknown. In this study, we examined if the association and subsequent membrane perforation induced by All was dependent on GM1 levels. Pretreatment of hippocampal neurons with DPDMP decreased GM1 and A beta clustering at the membrane (A beta fluorescent-punctas/20 mu m, control = 16.2 +/- 1.1 vs. DPDMP = 6.4 +/- 0.4, p < 0.001). Interestingly, membrane perforation with A beta occurred with a slower time course when the GM1 content was diminished (time to establish perforated configuration (TEPC) (min): control = 7.8 +/- 2 vs. low GM1 = 12.1 +/- 0.5, p < 0.01), suggesting that the presence of GM1 in the membrane can modulate the distribution and the membrane perforation by A beta. On the other hand, increasing GM1 facilitated the membrane perforation (TEPC: control = 7.8 +/- 2 vs. GM1 = 6.2 +/- 1 min, p < 0.05). Additionally, using Cholera Toxin Subunit-B (CTB) to block the interaction of A beta with GM1 attenuated membrane perforation significantly. Furthermore, pretreatment with CTB decreased the membrane association of AD (fluorescent-punctas/20 mu m, A beta: control = 14.8 +/- 2.5 vs. CTB = 8 +/- 1.4, p < 0.05), suggesting that GM1 also plays a role in both association of A beta with the membrane and in perforation. In addition, blockade of the AD association with CTB inhibited synaptotoxicity. Taken together, our results strongly suggest that membrane lipid composition can affect the ability of A beta to associate and subsequently perforate the plasma membrane thereby modulating its neurotoxicity in hippocampal neurons.