Efficacy of cyclin dependent kinase 4 inhibitors as potent neuroprotective agents against insults relevant to Alzheimer's disease.
Efficacy of cyclin dependent kinase 4 inhibitors as potent neuroprotective agents against insults relevant to Alzheimer's disease.
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DOI：
10.1371/journal.pone.0078842
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Biswas SC
中科院分区：
文献类型：
--
作者：
Sanphui P;Pramanik SK;Chatterjee N;Moorthi P;Banerji B;Biswas SC
阿尔茨海默病（Alzheimer's disease，AD）是一种进行性神经退行性疾病，至今仍无法治愈。细胞周期调节蛋白的异常激活与包括AD在内的神经退行性疾病有关。我们和其他人已经表明，细胞周期蛋白依赖性激酶4（Cdk 4）在AD脑中被激活，并且是神经元死亡所必需的。在这项研究中，我们测试了市售Cdk4特异性抑制剂的效率，以及一个小库的合成分子抑制剂靶向Cdk4作为神经元死亡的细胞模型中的神经保护剂。我们发现这些抑制剂中的几种显著保护神经元细胞免于由神经生长因子（NGF）剥夺和寡聚β淀粉样蛋白（Aβ）诱导的死亡，所述寡聚β淀粉样蛋白与AD有关。这些神经保护剂特异性地抑制Cdk4激酶活性、线粒体完整性的丧失、促凋亡蛋白Bim的诱导和响应于NGF剥夺的半胱天冬酶3活化。商业和合成抑制剂的功效是相当的。所合成的分子是菲基或萘基的，它们分别通过Pschorr反应和Buchwald偶联作为关键步骤之一合成。这两种分子都能有效地阻断神经变性。因此，我们建议Cdk4抑制剂将是改善AD神经变性的治疗选择，这些合成的Cdk4抑制剂可能导致开发有效的AD药物。
Alzheimer’s disease (AD) is a progressive neurodegenerative disease with no cure till today. Aberrant activation of cell cycle regulatory proteins is implicated in neurodegenerative diseases including AD. We and others have shown that Cyclin dependent kinase 4 (Cdk4) is activated in AD brain and is required for neuron death. In this study, we tested the efficiency of commercially available Cdk4 specific inhibitors as well as a small library of synthetic molecule inhibitors targeting Cdk4 as neuroprotective agents in cellular models of neuron death. We found that several of these inhibitors significantly protected neuronal cells against death induced by nerve growth factor (NGF) deprivation and oligomeric beta amyloid (Aβ) that are implicated in AD. These neuroprotective agents inhibit specifically Cdk4 kinase activity, loss of mitochondrial integrity, induction of pro-apoptotic protein Bim and caspase3 activation in response to NGF deprivation. The efficacies of commercial and synthesized inhibitors are comparable. The synthesized molecules are either phenanthrene based or naphthalene based and they are synthesized by using Pschorr reaction and Buchwald coupling respectively as one of the key steps. A number of molecules of both kinds block neurodegeneration effectively. Therefore, we propose that Cdk4 inhibition would be a therapeutic choice for ameliorating neurodegeneration in AD and these synthetic Cdk4 inhibitors could lead to development of effective drugs for AD.
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