Amyloid beta (Aβ) peptides represent one of the most studied etiological factors of Alzheimer's disease. Nevertheless, the effects elicited by different molecular forms of amyloid beta peptides widely vary between the studies, mostly depending on experimental conditions. Despite the enormous amount of accumulated evidences concerning the pathological effects of amyloid beta peptides, the exact identity of the amyloid beta species is still controversial, and even less is clear as regards to the downstream effectors that mediate the devastating impact of these peptides on synapses in the central nervous system. Recent publications indicate that some of the neurotoxic effects of amyloid beta peptides may be mediated via the activation of proteins belonging to the Abelson non-receptor tyrosine kinase (Abl) family, that are known to regulate actin cytoskeleton structure as well as phosphorylate microtubule-associated tau protein, a hallmark of Alzheimer's disease. By performing series of miniature excitatory postsynaptic currents (mEPSC) recordings in cultured hippocampal cells, we demonstrate that activation of Abl kinases by acute application of 42 amino acid-length monomeric amyloid beta (Aβ1-42) peptides reduces spontaneous synaptic release, while this effect can be rescued by pharmacologic inhibition of Abl kinase activity, or by reduction of Abl expression with small interfering RNAs. Our electrophysiological data are further reinforced by a subsequent biochemical analysis, showing enhanced phosphorylation of Abl kinase substrate CT10 Regulator of Kinase-homolog-Like (Crkl) upon treatment of hippocampal neurons with Aβ peptides. Thus, we conclude that Abl kinase activation may be involved in Aβ-induced weakening of synaptic transmission.

中文翻译：

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Abelson 激酶介导由淀粉样蛋白 1-42 肽诱导的自发突触活动的抑制。

淀粉样蛋白 β (Aβ) 肽是研究最多的阿尔茨海默病病因之一。然而，不同分子形式的淀粉样蛋白 β 肽引起的影响在研究之间差异很大，主要取决于实验条件。尽管积累了大量关于 β 淀粉样肽的病理学影响的证据，β 淀粉样蛋白种类的确切身份仍然存在争议，对于介导这些肽对突触的破坏性影响的下游效应子，则更不清楚。中枢神经系统。最近的出版物表明，淀粉样蛋白 β 肽的一些神经毒性作用可能是通过激活属于 Abelson 非受体酪氨酸激酶 (Abl) 家族的蛋白质来介导的，已知调节肌动蛋白细胞骨架结构以及磷酸化微管相关 tau 蛋白，这是阿尔茨海默病的标志。通过在培养的海马细胞中进行一系列微型兴奋性突触后电流 (mEPSC) 记录，我们证明了急性应用 42 个氨基酸长度的单体淀粉样蛋白 β (Aβ1-42) 肽激活 Abl 激酶会减少自发性突触释放，而这种作用可以通过药理学抑制 Abl 激酶活性或通过使用小干扰 RNA 减少 Abl 表达来挽救。我们的电生理数据通过随后的生化分析得到进一步加强，表明在用 Aβ 肽处理海马神经元后，Abl 激酶底物 CT10 激酶同源物样 (Crkl) 调节剂的磷酸化增强。因此，