Deregulated Cdk5 activity is involved in inducing Alzheimer's disease.
Deregulated Cdk5 activity is involved in inducing Alzheimer's disease.
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DOI：
10.1016/j.arcmed.2012.10.015
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发表时间：
2012-11
影响因子：
7.7
通讯作者：
Pant, Harish C.
中科院分区：
文献类型：
--
作者：
Shukla, Varsha;Skuntz, Susan;Pant, Harish C.
关键词：
阿尔茨海默病（AD）是成年人中最具破坏性的慢性神经退行性疾病，其导致痴呆并最终导致受影响个体的死亡。临床上，AD以迟发性、年龄依赖性认知功能减退为特征，其主要原因是大脑皮层和海马神经元的缺失。这些症状的病理结果是老年斑和神经纤维缠结的形成。老年斑是由于寡聚淀粉样蛋白β（Aβ）的积累形成的老年斑。这是由于各种分泌酶对淀粉样前体蛋白（APP）的淀粉样蛋白形成加工所致。另一方面，由于细胞骨架蛋白如tau和神经丝的过度磷酸化而形成神经纤维缠结。两者都被细胞周期蛋白依赖性激酶5（Cdk 5）过度磷酸化，是成对螺旋丝（PHF）的一部分，是神经元缠结的一个组成部分。与其他细胞周期蛋白依赖性激酶不同，Cdk 5在神经元发育中起着非常重要的作用。cdk 5被其神经元激活因子p35和p39激活。在应激时，p35和p39被钙蛋白酶切割，产生截短产物p25和p29。Cdk 5/p25的结合更长且不受控制，引起Cdk 5的各种底物如APP、tau和神经丝的异常过度磷酸化，导致神经退行性病理学如AD。此外，最近的证据表明，人类AD大脑中p25、Aβ水平升高，Cdk 5、磷酸化tau和神经丝过度活跃。本文就Cdk 5在AD发病机制中的作用进行了综述，并对Cdk 5作为AD治疗靶点的研究进展进行了总结。
Alzheimer’s disease (AD), the most devastating chronic neurodegenerative disease in adults, causes dementia and eventually, death of the affected individuals. Clinically, AD is characterized as late-onset, age-dependent cognitive decline due to loss of neurons in cortex and hippocampus. The pathologic corollary of these symptoms is the formation of senile plaques and neurofibrillary tangles. Senile plaques are formed due to accumulation of oligomeric amyloid beta (Aβ) forming fibrillary plaques. This occurs due to the amyloidogenic processing of the amyloid precursor protein (APP) by various secretases. On the other hand, neurofibrillary tangles are formed due to hyperphosphorylation of cytoskeleton proteins like tau and neurofilament. Both are hyperphosphorylated by cyclin-dependent kinase-5 (Cdk5) and are part of the paired helical filament (PHF), an integral part of neurofibrillary tangles. Unlike other cyclin-dependent kinases, Cdk5 plays a very important role in the neuronal development. Cdk5 gets activated by its neuronal activators p35 and p39. Upon stress, p35 and p39 are cleaved by calpain resulting in truncated products as p25 and p29. Association of Cdk5/p25 is longer and uncontrolled causing aberrant hyperphosphorylation of various substrates of Cdk5 like APP, tau and neurofilament, leading to neurodegenerative pathology like AD. Additionally recent evidence has shown increased levels of p25, Aβ, hyperactivity of Cdk5, phosphorylated tau and neurofilament in human AD brains. This review briefly describes the above-mentioned aspects of involvement of Cdk5 in the pathology of AD and at the end summarizes the advances in Cdk5 as a therapeutic target.
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DOI：
10.1523/jneurosci.5874-09.2010
发表时间：
2010-04-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
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作者：
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DOI：
10.1073/pnas.85.11.4051
发表时间：
1988-06-01
影响因子：
11.1
作者：
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通讯作者：
KLUG, A
DOI：
10.1073/pnas.89.22.10867
发表时间：
1992-11-15
影响因子：
11.1
作者：
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