Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
Neurobiol Aging. 2012 Feb;33(2):254-64. doi: 10.1016/j.neurobiolaging.2010.01.016. Epub 2010 Feb 5.
A chronic neuron loss is the cardinal pathology in Alzheimer disease (AD), but it is still not understood why most neurons in AD brain do not accomplish apoptosis even though they are actually exposed to an environment with enriched proapoptotic factors. Protein phosphatase-2A inhibitor-2 (I(2)(PP2A)), an endogenous PP2A inhibitor, is significantly increased in AD brain, but the role of I(2)(PP2A) in AD-like neuron loss is elusive. Here, we show that I(2)(PP2A) regulates p53 and Akt correlatively. The mechanisms involve activated transcription and p38 MAPK activities. More importantly, we demonstrate that the simultaneous activation of Akt induced by I(2)(PP2A) counteracts the hyperactivated p53-induced cell apoptosis. Furthermore, I(2)(PP2A), p53 and Akt are all elevated in the brain of mouse model and AD patients. Our results suggest that the increased I(2)(PP2A) may trigger apoptosis by p53 upregulation, but due to simultaneous activation of Akt, the neurons are aborted from the apoptotic pathway. This finding contributes to the understanding of why most neurons in AD brain do not undergo apoptosis.
慢性神经元丢失是阿尔茨海默病（AD）的主要病理学特征，但目前仍不清楚为什么 AD 大脑中的大多数神经元尽管实际上暴露于富含促凋亡因子的环境中，但仍未完成细胞凋亡。蛋白磷酸酶-2A 抑制剂-2（I（2）（PP2A））是一种内源性的 PP2A 抑制剂，在 AD 大脑中显著增加，但 I（2）（PP2A）在 AD 样神经元丢失中的作用仍不清楚。在这里，我们表明 I（2）（PP2A）可协同调节 p53 和 Akt。其机制涉及激活转录和 p38 MAPK 活性。更重要的是，我们证明 I（2）（PP2A）诱导的 Akt 同时激活可拮抗过度激活的 p53 诱导的细胞凋亡。此外，I（2）（PP2A）、p53 和 Akt 在小鼠模型和 AD 患者的大脑中均升高。我们的研究结果表明，增加的 I（2）（PP2A）可能通过上调 p53 引发细胞凋亡，但由于 Akt 的同时激活，神经元从凋亡途径中止。这一发现有助于理解为什么 AD 大脑中的大多数神经元不发生凋亡。
