A new molecular link between the fibrillar and granulovacuolar lesions of Alzheimer's disease
A new molecular link between the fibrillar and granulovacuolar lesions of Alzheimer's disease
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DOI：
10.1016/s0002-9440(10)65219-4
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发表时间：
1999-10-01
影响因子：
6
通讯作者：
Kuret, J
中科院分区：
文献类型：
--
作者：
Ghoshal, N;Smiley, JF;Kuret, J
阿尔茨海默病（AD）是一种进行性神经退行性疾病，涉及海马、新皮层和大脑其他区域的特定神经元。终末期疾病的标志包括纤维状病变，纤维状病变积聚了聚合成细丝的过度磷酸化的tau蛋白，以及颗粒空泡性病变，主要出现在海马体内。只有特定的神经元群才会发生这些损伤的机制以及它们之间的关系尚不清楚。为了解决这些问题，我们转向阿尔茨海默病组织寻找特异性参与tau过度磷酸化的酶。最近，我们发现与AD脑源性tau蛋白丝相关的主要磷酸转移酶是酪蛋白激酶-1 （CK1）蛋白激酶家族的成员，在这里，我们报告了三种CK1亚型（Cki α， Cki δ和Cki epsilon）在AD和对照大脑中的分布。除了与原纤维病理元素共定位外，CK1还存在于颗粒空泡变性小体的基质中。此外，与对照组相比，AD海马CA1区所有CK1亚型的水平均升高，其中一种亚型Cki δ的水平升高了30倍。我们认为该蛋白激酶家族的过表达在tau蛋白的过度磷酸化和ad相关病理的形成中起着关键作用。
Alzheimer's Disease (AD) is a progressive neurodegenerative disorder involving select neurons of the hippocampus, neocortex, and other regions of the brain. Markers of end stage disease include fibrillar lesions, which accumulate hyperphosphorylated tau protein polymerized into filaments, and granulovacuolar lesions, which appear primarily within the hippocampus. The mechanism by which only select populations of neurons develop these lesions as well as the relationship between them is unknown. To address these questions, we have turned to AD tissue to search for enzymes specifically involved in tau hyperphosphorylation. Recently, we showed that the principal phosphotransferases associated with AD brain-derived tau filaments are members of the casein kinase-1 (CK1) family of protein kinases, Here we report the distribution of three CK1 isoforms (Cki alpha, Cki delta, and Cki epsilon) in AD and control brains using immunohistochemistry and Western analysis. In addition to colocalizing with elements of the fibrillar pathology, CK1 is found within the matrix of granulovacuolar degeneration bodies. Furthermore, levels of all CK1 isoforms are elevated in the CA1 region of AD hippocampus relative to controls, with one isoform, Cki delta, being elevated >30-fold. We propose that overexpression of this protein kinase family plays a key role in the hyperphosphorylation of tau and in the formation of AD-related pathology.