Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology
Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology
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DOI：
10.1111/j.1471-4159.2004.02949.x
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发表时间：
2005-04-01
影响因子：
4.7
通讯作者：
O'Neill, C
中科院分区：
文献类型：
--
作者：
Griffin, RJ;Moloney, A;O'Neill, C
研究表明，磷酸肌醇3-激酶-Akt的激活可以防止阿尔茨海默病（AD）中的神经元细胞死亡。然而，在这里，我们提供了证据，增加Akt激活，和AD脑中关键Akt底物的过度磷酸化，这与AD发病机制有关，这表明需要仔细考虑旨在激活AD通路的治疗。与对照组相比，AD颞叶皮层神经元中检测到Akt和磷酸化Akt的不同分布，颗粒组分中活性磷酸化Akt水平升高，AD胞质组分中Akt水平显著降低，导致AD中Akt活化（磷酸化Akt/总Akt比率）增加。与对照组相比，AD颞叶皮质中总Akt底物磷酸化水平显著升高，包括：GSK 3 β（Ser 9）、tau（Ser 214）、mTOR（Ser 2448），Akt靶点p27（kip 1）水平降低。在AD神经元中也检测到Akt的主要负调节因子PTEN（10号染色体上缺失的磷酸酶和张力蛋白同源物）的显著损失和分布改变。AD末期海马CA 1区磷酸化Akt和PTEN阳性神经元缺失。总之，这些结果支持Akt和PTEN信号传导的异常控制在AD中的潜在作用。
Studies suggest that activation of phosphoinositide 3- kinase-Akt may protect against neuronal cell death in Alzheimer's disease (AD). Here, however, we provide evidence of increased Akt activation, and hyperphosphorylation of critical Akt substrates in AD brain, which link to AD pathogenesis, suggesting that treatments aiming to activate the pathway in AD need to be considered carefully. A different distribution of Akt and phospho-Akt was detected in AD temporal cortex neurons compared with control neurons, with increased levels of active phosphorylated-Akt in particulate fractions, and significant decreases in Akt levels in AD cytosolic fractions, causing increased activation of Akt (phosphorylated-Akt/total Akt ratio) in AD. In concordance, significant increases in the levels of phosphorylation of total Akt substrates, including: GSK3 beta(Ser9), tau(Ser214), mTOR(Ser2448), and decreased levels of the Akt target, p27(kip1), were found in AD temporal cortex compared with controls. A significant loss and altered distribution of the major negative regulator of Akt, PTEN (phosphatase and tensin homologue deleted on chromosome 10), was also detected in AD neurons. Loss of phosphorylated-Akt and PTEN-containing neurons were found in hippocampal CA1 at end stages of AD. Taken together, these results support a potential role for aberrant control of Akt and PTEN signalling in AD.