Monaco E A
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
Curr Alzheimer Res. 2004 Feb;1(1):33-8. doi: 10.2174/1567205043480519.
Based on a growing literature, cyclin-dependent kinase 5 (Cdk5) has been implicated in the pathological processes that contribute to neurodegeneration in Alzheimer's disease (AD). Cdk5 is ubiquitously expressed, but its activity is largely localized to post-mitotic neurons due to neuron-specific expression of its activators p35 and p39. Sufficient Cdk5 activity is critical to normal central nervous system development, as in its absence, neuronal migration and axonal path finding are deranged. Conversely, excessive and mislocalized Cdk5 activity appears to be detrimental to neuronal function. In fact, the pathological hallmarks of AD, beta-amyloid aggregates and neurofibrillary tangles, have been linked to Cdk5-mediated neuronal death. In this model, beta-amyloid is the toxic stimulus that disrupts intracellular calcium homeostasis, leading to activation of calpains, a family of calcium-dependent proteases. Calpain-mediated cleavage of p35, yields a truncated p25 fragment that possesses a longer half-life, lacks the necessary sequence targeting it to membranes, but retains the capacity to activate Cdk5. The resulting excessive and mislocalized Cdk5 activity targets tau as a substrate for hyperphosphorylation, which is a prerequisite of paired helical filament (PHF) formation. A number of recent reports, utilizing diverse methods, lend further support to this model of AD neurodegeneration, and several strategies for combating Cdk5 dysregulation have even been devised. However, the study of Cdk5 in AD is not without controversy, and questions remain regarding its role in the pathology. Herein, the most recent findings regarding this model are reviewed.
基于越来越多的文献，细胞周期蛋白依赖性激酶5（Cdk5）已被认为参与了导致阿尔茨海默病（AD）神经退行性变的病理过程。Cdk5在全身广泛表达，但其活性主要定位于有丝分裂后的神经元，这是由于其激活剂p35和p39在神经元中特异性表达。足够的Cdk5活性对正常中枢神经系统发育至关重要，因为在其缺失时，神经元迁移和轴突寻路会紊乱。相反，Cdk5活性过高和定位错误似乎对神经元功能有害。事实上，AD的病理特征，即β-淀粉样蛋白聚集体和神经原纤维缠结，已与Cdk5介导的神经元死亡相关。在这个模型中，β-淀粉样蛋白是破坏细胞内钙稳态的毒性刺激物，导致钙蛋白酶（一类钙依赖性蛋白酶）的激活。钙蛋白酶介导的p35裂解产生一个截短的p25片段，该片段具有更长的半衰期，缺乏将其靶向细胞膜的必要序列，但保留了激活Cdk5的能力。由此产生的过高和定位错误的Cdk5活性将tau作为过度磷酸化的底物，这是双螺旋丝（PHF）形成的先决条件。最近的一些报告利用多种方法，进一步支持了这种AD神经退行性变模型，甚至还设计了几种对抗Cdk5失调的策略。然而，对AD中Cdk5的研究并非没有争议，关于其在病理中的作用仍存在疑问。在此，对关于该模型的最新发现进行综述。
