Michaelis M L, Ansar S, Chen Y, Reiff E R, Seyb K I, Himes R H, Audus K L, Georg G I
Department of Pharmacology and Toxicology, 1251 Wescoe Hall Dr., 5064 Malott Hall, University of Kansas, Lawrence, KS 66045, USA.
J Pharmacol Exp Ther. 2005 Feb;312(2):659-68. doi: 10.1124/jpet.104.074450. Epub 2004 Sep 16.
Deposition of beta-amyloid peptide (Abeta) and hyperphosphorylation of the tau protein are associated with neuronal dysfunction and cell death in Alzheimer's disease. Although the relationship between these two processes is not yet understood, studies have shown that both in vitro and in vivo exposure of neurons to Abeta leads to tau hyperphosphorylation and neuronal dystrophy. We previously reported that the microtubule-stabilizing drug paclitaxel (Taxol) protects primary neurons against toxicity induced by the Abeta(25-35) peptide. The studies in this report were undertaken to characterize the actions of paclitaxel more fully, to assess the effectiveness of structurally diverse microtubulestabilizing agents in protecting neurons, and to determine the time course of the protective effects of the drugs. Primary neurons were exposed to Abeta in the presence or absence of several agents shown to interact with microtubules, and neuronal survival was monitored. Paclitaxel protected neurons against Abeta(1-42) toxicity, and paclitaxel-treated cultures exposed to Abeta showed enhanced survival over Abeta-only cultures for several days. Neuronal apoptosis induced by Abeta was blocked by paclitaxel. Other taxanes and three structurally diverse microtubule-stabilizing compounds also significantly increased survival of Abeta-treated cultures. At concentrations below 100 nM, the drugs that protected the neurons did not produce detectable toxicity when added to the cultures alone. Although multiple mechanisms are likely to contribute to the neuronal cell death induced by oligomeric or fibrillar forms of Abeta, low concentrations of drugs that preserve the integrity of the cytoskeletal network may help neurons survive the toxic cascades initiated by these peptides.
β-淀粉样肽（Aβ）的沉积和tau蛋白的过度磷酸化与阿尔茨海默病中的神经元功能障碍和细胞死亡有关。尽管这两个过程之间的关系尚不清楚，但研究表明，在体外和体内，神经元暴露于Aβ都会导致tau蛋白过度磷酸化和神经元营养不良。我们之前报道过，微管稳定剂紫杉醇（泰素）可保护原代神经元免受Aβ（25-35）肽诱导的毒性。本报告中的研究旨在更全面地描述紫杉醇的作用，评估结构多样的微管稳定剂保护神经元的有效性，并确定药物保护作用的时间进程。在有或没有几种显示与微管相互作用的药物存在的情况下，将原代神经元暴露于Aβ，并监测神经元的存活情况。紫杉醇保护神经元免受Aβ（1-42）毒性，在暴露于Aβ的情况下，用紫杉醇处理的培养物在数天内比仅暴露于Aβ的培养物显示出更高的存活率。紫杉醇可阻断由Aβ诱导的神经元凋亡。其他紫杉烷类药物和三种结构多样的微管稳定化合物也显著提高了经Aβ处理的培养物的存活率。在浓度低于100 nM时，保护神经元的药物单独添加到培养物中时不会产生可检测到的毒性。尽管多种机制可能导致由寡聚体或纤维状形式的Aβ诱导的神经元细胞死亡，但低浓度的保持细胞骨架网络完整性的药物可能有助于神经元在这些肽引发的毒性级联反应中存活下来。
