The PI3K-Akt-mTOR pathway regulates Abeta oligomer induced neuronal cell cycle events.
The PI3K-Akt-mTOR pathway regulates Abeta oligomer induced neuronal cell cycle events.
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DOI：
10.1186/1750-1326-4-14
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发表时间：
2009-03-16
影响因子：
15.1
通讯作者：
Lamb BT
中科院分区：
文献类型：
--
作者：
Bhaskar K;Miller M;Chludzinski A;Herrup K;Zagorski M;Lamb BT
越来越多的证据表明，阿尔茨海默病（AD）中易于变性的神经元表现出重新进入异常有丝分裂细胞周期的证据。我们的实验室最近证明，在AD（R1.40）的基因组淀粉样前体蛋白（APP）小鼠模型中，神经元细胞周期事件（CCE）在β-淀粉样蛋白（Aβ）沉积不存在的情况下发生，并且仍然依赖于淀粉样前体蛋白（APP）的淀粉样蛋白形成过程。这些数据表明，可溶性Aβ物质可能在神经元CCE的诱导中起直接作用。在这里，我们表明，非转基因原代皮层神经元暴露于Aβ寡聚体，而不是单体或原纤维，导致神经元突起的收缩，并以浓度依赖性方式诱导CCE。神经元突起的收缩与CCE的诱导相关，Aβ单体或Aβ原纤维仅显示出极轻微的影响。此外，我们提供的证据表明，诱导神经元CCE是自主的原代神经元培养的R1.40小鼠。最后，我们的研究结果还表明，Aβ寡聚体处理的神经元表现出激活的Akt和mTOR（哺乳动物雷帕霉素靶标）水平升高，并且PI 3 K、Akt或mTOR抑制剂阻断了Aβ寡聚体诱导的神经元CCE。总之，这些结果表明，基于Aβ寡聚体的神经元CCE诱导涉及PI 3 K-Akt-mTOR通路。
Accumulating evidence suggests that neurons prone to degeneration in Alzheimer's Disease (AD) exhibit evidence of re-entry into an aberrant mitotic cell cycle. Our laboratory recently demonstrated that, in a genomic amyloid precursor protein (APP) mouse model of AD (R1.40), neuronal cell cycle events (CCEs) occur in the absence of beta-amyloid (Aβ) deposition and are still dependent upon the amyloidogenic processing of the amyloid precursor protein (APP). These data suggested that soluble Aβ species might play a direct role in the induction of neuronal CCEs. Here, we show that exposure of non-transgenic primary cortical neurons to Aβ oligomers, but not monomers or fibrils, results in the retraction of neuronal processes, and induction of CCEs in a concentration dependent manner. Retraction of neuronal processes correlated with the induction of CCEs and the Aβ monomer or Aβ fibrils showed only minimal effects. In addition, we provide evidence that induction of neuronal CCEs are autonomous to primary neurons cultured from the R1.40 mice. Finally, our results also demonstrate that Aβ oligomer treated neurons exhibit elevated levels of activated Akt and mTOR (mammalian Target Of Rapamycin) and that PI3K, Akt or mTOR inhibitors blocked Aβ oligomer-induced neuronal CCEs. Taken together, these results demonstrate that Aβ oligomer-based induction of neuronal CCEs involve the PI3K-Akt-mTOR pathway.
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DOI：
10.1016/j.bbadis.2006.09.010
发表时间：
2007-04-01
影响因子：
6.2
作者：
McShea, Andrew;Lee, Hyoung-gon;Smith, Mark A.
通讯作者：
Smith, Mark A.
影响因子：
5.3
作者：
Andorfer, C;Acker, CM;Davies, P
通讯作者：
Davies, P
影响因子：
5.4
作者：
Li, X;Alafuzoff, I;Pei, JJ
通讯作者：
Pei, JJ
影响因子：
4.7
作者：
Malik, Bilal;Currais, Antonio;Soriano, Salvador
通讯作者：
Soriano, Salvador
影响因子：
16.2
作者：
Calon, F;Lim, GP;Cole, GM
通讯作者：
Cole, GM