Accumulation of tumor-suppressor PTEN in Alzheimer neurofibrillary tangles
Accumulation of tumor-suppressor PTEN in Alzheimer neurofibrillary tangles
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DOI：
10.1016/j.neulet.2009.12.078
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发表时间：
2010-02
影响因子：
2.5
通讯作者：
Yuma Sonoda;H. Mukai;K. Matsuo;Mikiko Takahashi;Y. Ono;K. Maeda;H. Akiyama;T. Kawamata
中科院分区：
文献类型：
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作者：
Yuma Sonoda;H. Mukai;K. Matsuo;Mikiko Takahashi;Y. Ono;K. Maeda;H. Akiyama;T. Kawamata
10号染色体上缺失的磷酸酶和紧张素同源物（PTEN）负调控细胞内PIP3水平，并拮抗对细胞存活重要的PI3K信号通路。目前的研究确定了PTEN分布的改变是否发生在阿尔茨海默病（AD）的大脑中。我们利用免疫印迹和显微镜分析研究了PTEN在老年对照和AD患者死后脑组织中的可能作用。在锥体细胞等大神经元中发现了强烈的免疫标记。在正常神经元中，PTEN位于细胞核、细胞体的细胞质和顶端树突的近端。在阿尔茨海默病的其余神经元中，PTEN的表达和再分布减少。此外，PTEN在受损神经元中从细胞核和细胞质重新分布到AD海马、枕下、内皮层和角回老年斑内的细胞内神经原纤维缠结（nft）、神经丝和营养不良的神经突等神经病变。此外，双免疫荧光染色显示细胞内nft双标记PTEN和tau，部分轴突标记PTEN和磷酸化的神经丝，老年斑周围少数反应性星形胶质细胞弱标记PTEN和GFAP。在缠结神经元亚群中观察到PTEN和GSK3β或PTEN和MEK的nft双标记。因此，我们的研究结果表明，PTEN从细胞核到细胞质和细胞内nft的脱位可能导致细胞质中PI3K通路的失调，并可能导致AD退行性神经元中PTEN的核功能障碍。
The phosphatase and tensin homologue deleted on chromosome 10 (PTEN) negatively regulates intracellular levels of PIP3 and antagonizes the PI3K signaling pathway important for cell survival. The present study determined whether altered distribution of PTEN occurs in Alzheimer's disease (AD) brains. We investigated a possible role for PTEN in postmortem brain tissues from elderly controls and patients with AD using immunoblotting and microscopic analyses. Intense immunolabeling was found in the large neurons such as pyramidal cells. In normal neurons, PTEN was located in the nucleus, the cytoplasm of cell bodies and the proximal portion of apical dendrites. Reduced expression and redistribution of PTEN was seen in the remaining neurons in AD. In addition, PTEN was redistributed in damaged neurons from the nucleus and cytoplasm to neuritic pathology such as intracellular neurofibrillary tangles (NFTs), neuropil threads and dystrophic neurites within senile plaques in AD hippocampus, subiculum, entorhinal cortex and angular gyrus. Furthermore, double immunofluorescence staining showed dual labeling of intracellular NFTs for PTEN and tau, labeling of some axons for PTEN and phosphorylated neurofilament, and weak labeling of a few reactive astrocytes around senile plaques for PTEN and GFAP. Double labeling of NFTs was observed in a subset of tangle-bearing neurons either for PTEN and GSK3β or for PTEN and MEK. Thus our results suggest that PTEN delocalized from the nucleus to the cytoplasm and to intracellular NFTs may cause a deregulation of PI3K pathway in the cytoplasm and may induce the nuclear dysfunction of PTEN in AD degenerating neurons.