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首页> 外文期刊>The European Journal of Neuroscience >Memantine protects rat cortical cultured neurons against beta-amyloid-induced toxicity by attenuating tau phosphorylation.
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Memantine protects rat cortical cultured neurons against beta-amyloid-induced toxicity by attenuating tau phosphorylation.

机译：美金刚胺通过减弱tau磷酸化来保护大鼠皮质培养的神经元免受β-淀粉样蛋白诱导的毒性。

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It has been suggested that accumulation of beta-amyloid (Abeta) peptide triggers neurodegeneration, at least in part, via glutamate-mediated excitotoxicity in Alzheimer's disease (AD) brain. This is supported by observations that toxicity induced by Abeta peptide in cultured neurons and in adult rat brain is known to be mediated by activation of glutamatergic N-methyl-d-aspartate (NMDA) receptors. Additionally, recent clinical studies have shown that memantine, a noncompetitive NMDA receptor antagonist, can significantly improve cognitive functions in some AD patients. However, very little is currently known about the potential role of memantine against Abeta-induced toxicity. In the present study, we have shown that Abeta(1-42)-induced toxicity in rat primary cortical cultured neurons is accompanied by increased extracellular and decreased intracellular glutamate levels. We subsequently demonstrated that Abeta toxicity is induced by increased phosphorylation of tau protein and activation of tau kinases, i.e. glycogen synthase kinase-3beta and extracellular signal-related kinase 1/2. Additionally, Abeta treatment induced cleavage of caspase-3 and decreased phosphorylation of cyclic AMP response element binding protein, which are critical in determining survival of neurons. Memantine treatment significantly protected cultured neurons against Abeta-induced toxicity by attenuating tau-phosphorylation and its associated signaling mechanisms. However, this drug did not alter either conformation or internalization of Abeta(1-42) and it was unable to attenuate Abeta-induced potentiation of extracellular glutamate levels. These results, taken together, provide new insights into the possible neuroprotective action of memantine in AD pathology.
机译：已经提出，β-淀粉样蛋白（Aβ）肽的积累至少部分通过谷氨酸介导的阿尔茨海默氏病（AD）脑中的兴奋性毒性触发神经变性。观察到的证据支持了这一点，已知Abeta肽在培养的神经元和成年大鼠脑中诱导的毒性是通过激活谷氨酸能N-甲基-d-天冬氨酸（NMDA）受体介导的。此外，最近的临床研究表明，非竞争性NMDA受体拮抗剂美金刚可以显着改善某些AD患者的认知功能。然而，目前关于美金刚对Abeta诱导的毒性的潜在作用知之甚少。在本研究中，我们已经表明，Abeta（1-42）诱导的大鼠原代皮层培养神经元的毒性伴随着细胞外和谷氨酸水平的升高。我们随后证明，通过增加tau蛋白的磷酸化和tau激酶（即糖原合酶激酶3beta和细胞外信号相关激酶1/2）的活化，可以诱导Abeta毒性。此外，Abeta处理诱导caspase-3的切割和环状AMP响应元件结合蛋白的磷酸化降低，这对确定神经元的存活至关重要。美金刚胺治疗通过减弱tau-磷酸化作用及其相关信号传导机制，显着保护培养的神经元免受Abeta诱导的毒性。但是，这种药物不会改变Abeta（1-42）的构象或内在化，并且不能减弱Abeta诱导的细胞外谷氨酸水平的增强。这些结果加在一起，为美金刚在AD病理中可能的神经保护作用提供了新的见解。

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