β-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand
β-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand
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DOI：
10.1523/jneurosci.21-19-07551.2001
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发表时间：
2001-10-01
影响因子：
5.3
通讯作者：
Greenberg, ME
中科院分区：
文献类型：
--
作者：
Morishima, Y;Gotoh, Y;Greenberg, ME
β-淀粉样蛋白（A β）水平升高存在于患有散发性或家族性阿尔茨海默病（AD）的个体的脑中，并且作为AD标志的老年斑内A β的沉积被认为是AD中发生的认知功能障碍的主要原因。最近的证据表明，A β诱导脑和原代神经元培养物中的神经元凋亡，并且这种A β诱导的神经元死亡可能是AD患者中发现的认知下降的部分原因。在这项研究中，我们的特点是一种机制，其中A β诱导神经元死亡。我们发现，在暴露于A β的皮质神经元中，激活的c-Jun N-末端激酶（JNK）是c-Jun转录因子磷酸化和激活所必需的，这反过来又刺激了几个关键靶基因的转录，包括死亡诱导因子Fas配体。Fas配体与其受体Fas的结合然后诱导导致半胱天冬酶活化和最终细胞死亡的级联反应。通过分析JNK-c-Jun-Fas配体-Fas通路的每个组分中的突变的影响，我们证明了该通路在介导AP诱导的培养神经元死亡中起着关键作用。这些发现提高了JNK途径也可能导致AD患者A β依赖性死亡的可能性。
Elevated levels of beta -Amyloid (A beta) are present in the brains of individuals with either the sporadic or familial form of Alzheimer's disease (AD), and the deposition of A beta within the senile plaques that are a hallmark of AD is thought to be a primary cause of the cognitive dysfunction that occurs in AD. Recent evidence suggests that A beta induces neuronal apoptosis in the brain and in primary neuronal cultures, and that this A beta -induced neuronal death may be responsible in part for the cognitive decline found in AD patients. In this study we have characterized one mechanism by which A beta induces neuronal death. We found that in cortical neurons exposed to A beta, activated c-Jun N-terminal kinase (JNK) is required for the phosphorylation and activation of the c-Jun transcription factor, which in turn stimulates the transcription of several key target genes, including the death inducer Fas ligand. The binding of Fas ligand to its receptor Fas then induces a cascade of events that lead to caspase activation and ultimately cell death. By analyzing the effects of mutations in each of the components of the JNK-c-Jun-Fas ligand-Fas pathway, we demonstrate that this pathway plays a critical role in mediating Ap-induced death of cultured neurons. These findings raise the possibility that the JNK pathway may also contribute to A beta -dependent death in AD patients.