Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe 654-0142, Japan.
Neurosci Lett. 2010 Feb 26;471(1):20-4. doi: 10.1016/j.neulet.2009.12.078. Epub 2010 Jan 5.
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 GSK3beta 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.
第 10 号染色体缺失的磷酸酶和张力蛋白同系物（PTEN）负向调节细胞内 PIP3 的水平，并拮抗对细胞存活至关重要的 PI3K 信号通路。本研究旨在确定 PTEN 在阿尔茨海默病（AD）脑中的分布是否发生改变。我们使用免疫印迹和显微镜分析，研究了 PTEN 在老年对照组和 AD 患者死后脑组织中的可能作用。在大神经元（如锥体细胞）中发现了强烈的免疫标记。在正常神经元中，PTEN 位于细胞核、细胞体的细胞质和树突的近端部分。在 AD 中，剩余神经元中可见 PTEN 表达减少和重新分布。此外，PTEN 在受损神经元中的分布从细胞核和细胞质重新分布到神经纤维缠结（NFT）等神经内病理学中，AD 海马体、下托、内嗅皮层和角回中的神经原纤维缠结、神经丝缠结和神经突。此外，双免疫荧光染色显示，PTEN 和 tau 标记神经元内 NFT 的双标记，PTEN 和磷酸化神经丝标记一些轴突，以及老年斑块周围的少数反应性星形胶质细胞标记 PTEN 和 GFAP。在具有 NFT 的神经元亚群中观察到 NFT 的双标记，用于 PTEN 和 GSK3beta 或用于 PTEN 和 MEK。因此，我们的结果表明，PTEN 从细胞核易位到细胞质和细胞内 NFT 可能导致 PI3K 通路在细胞质中失调，并可能导致 AD 退化神经元中 PTEN 的核功能障碍。
