One neurotoxic mechanism of amyloid-beta peptide (Aβ), the major component of senile plaques in the brains of Alzheimer's disease (AD) patients, is to trigger cell cycle reentry in fully differentiated neurons. However, the detailed underlying mechanisms remain unclear. Using Aβ25-35-treated primary rat cortical neurons as the experimental system, in the present study we tested whether Aβ-induced inhibitor of differentiation-1 (Id1)/hypoxia-inducible factor-1alpha (HIF-1α) and cyclin-dependent kinase-5 (CDK5) contribute to cell cycle reentry in fully differentiated post-mitotic neurons. We found that Id1-induced HIF-1α mediated Aβ25-35-dependent expression of the cell cycle markers cyclin D1 and proliferating cell nuclear antigen (PCNA), both colocalized with microtubule-associated protein-2 (MAP-2) + cells, indicative of cell cycle reentry in the mature neurons. Aβ25-35 also enhanced p35 cleavage to p25 without affecting CDK5 expression. The CDK5 inhibitor roscovitine and the siRNA targeting CDK5 both suppressed Aβ25-35-dependent HIF-1α expression and cell cycle reentry. Intriguingly, Aβ25-35-induced Id1 repressed p25 production while CDK5/p25 reciprocally inhibited Id1 expression, despite the observation that both Id1 and CDK5/p25 acted upstream of HIF-1α. These results demonstrated that both Id1/HIF-1 and CDK5/HIF-1 contribute to Aβ-induced cell cycle reentry in post-mitotic neurons; furthermore, Id1 and CDK5/p25 reciprocally suppress expression of each other.

中文翻译：

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Id1 / HIF-1和CDK5 / HIF-1在有丝分裂后皮质神经元中淀粉样β肽诱导的细胞周期再进入中的作用。

阿尔茨海默氏病（AD）患者大脑中老年斑的主要成分之一-淀粉样-β肽（Aβ）的一种神经毒性机制是触发完全分化的神经元的细胞周期再进入。但是，具体的潜在机制仍不清楚。以Aβ25-35处理的原代大鼠皮层神经元为实验系统，在本研究中，我们测试了Aβ诱导的分化抑制剂1（Id1）/缺氧诱导因子1α（HIF-1α）和细胞周期蛋白依赖性激酶-5（CDK5）在完全分化的有丝分裂后神经元中促进细胞周期的再进入。我们发现，Id1诱导的HIF-1α介导了细胞周期标记物cyclin D1和增殖细胞核抗原（PCNA）的Aβ25-35依赖性表达，二者均与微管相关蛋白2（MAP-2）+细胞共定位，指示成熟神经元中细胞周期的折返。Aβ25-35还增强了p35对p25的切割，而不会影响CDK5的表达。CDK5抑制剂roscovitine和靶向CDK5的siRNA均抑制Aβ25-35依赖性HIF-1α表达和细胞周期再进入。有趣的是，尽管观察到Id1和CDK5 / p25都在HIF-1α的上游起作用，但Aβ25-35诱导的Id1抑制了p25的产生，而CDK5 / p25却抑制了Id1的表达。这些结果表明，Id1 / HIF-1和CDK5 / HIF-1均参与有丝分裂后神经元中Aβ诱导的细胞周期再进入。此外，Id1和CDK5 / p25相互抑制彼此的表达。CDK5抑制剂roscovitine和靶向CDK5的siRNA均抑制Aβ25-35依赖性HIF-1α表达和细胞周期再进入。有趣的是，尽管观察到Id1和CDK5 / p25都在HIF-1α的上游起作用，但Aβ25-35诱导的Id1抑制了p25的产生，而CDK5 / p25却抑制了Id1的表达。这些结果表明，Id1 / HIF-1和CDK5 / HIF-1均参与有丝分裂后神经元中Aβ诱导的细胞周期再进入。此外，Id1和CDK5 / p25相互抑制彼此的表达。CDK5抑制剂roscovitine和靶向CDK5的siRNA均抑制Aβ25-35依赖性HIF-1α表达和细胞周期再进入。有趣的是，尽管观察到Id1和CDK5 / p25都在HIF-1α的上游起作用，但Aβ25-35诱导的Id1抑制了p25的产生，而CDK5 / p25却抑制了Id1的表达。这些结果表明，Id1 / HIF-1和CDK5 / HIF-1均参与有丝分裂后神经元中Aβ诱导的细胞周期再进入。此外，Id1和CDK5 / p25相互抑制彼此的表达。这些结果表明，Id1 / HIF-1和CDK5 / HIF-1均参与有丝分裂后神经元中Aβ诱导的细胞周期再进入。此外，Id1和CDK5 / p25相互抑制彼此的表达。这些结果表明，Id1 / HIF-1和CDK5 / HIF-1均参与有丝分裂后神经元中Aβ诱导的细胞周期再进入。此外，Id1和CDK5 / p25相互抑制彼此的表达。