CIP2A对星形胶质细胞活化调控及其突触损伤机制研究

A1 type astrogliosis-induced synaptic deficit plays a key role in AD development, with the underlying mechanism remains unclear. Our preliminary data showed that CIP2A increased its level in reactive astrocytes in AD brains; upregulation of CIP2A resulted in proliferation and activation of astrocytes, which further secreted toxic factors and induced synaptic degeneration of co-cultured neurons; inhibition of Akt could reverse the proliferation of astrocytes induced by CIP2A. Based on these data, we hypothesize that CIP2A promotes A1 type astrogliosis through activating Akt, thus mediates synaptic impairment. To identify this hypothesis, we will 1) compare the difference of astrogliosis between wild type and CIP2A astrocyte conditional KO mice which were injected with LPS; 2) explore the astrogliosis and synaptic structure/function in astrocyte-specific CIP2A overexpressed animal brain or astrocyte/neuron co-culture system, with or without Akt ShRNA/ Akt inhibitor; 3) to explore the rescue effect of CIP2A ShRNA lenti-virus or inhibitor on astrogliosis and synaptic impairment in AD animal models. Studies from this project will disclose the effect and mechanisms of CIP2A in promoting reactive astrogliosis, thus provide new molecular target for AD treatment.

星形胶质细胞A1型活化导致突触损伤在AD中起关键作用而机制不明。申请者研究发现CIP2A在AD脑内水平增加且定位于活化的星胶细胞，在星胶上调CIP2A可导致其增殖活化，分泌损伤因子且导致共培养的神经元突触退变；干预Akt活性可逆转CIP2A导致的星胶增殖。基于以上背景，我们提出CIP2A通过激活Akt导致星胶A1型活化，从而介导突触损伤。本项目拟1)比较野生型和CIP2A星胶条件敲除鼠注射LPS后星胶活化差异2) 整体动物脑内和星胶／神经元共培养系统通过病毒特异性星胶过表达CIP2A，同时过表达Akt ShRNA或使用Akt抑制剂阻断Akt激活，检测星胶活化和突触结构功能3) 在AD模型动物通过基因或药物干预下调CIP2A探讨其对星胶活化和突触损伤的逆转效应。研究将从细胞和整体水平阐明CIP2A促进星形胶质细胞反应性活化的作用和分子机制, 为早期防治AD提供新的分子靶点。

星形胶质细胞A1型活化导致突触损伤在AD中起关键作用而机制不明。我们的前期研究发现CIP2A在AD脑内水平增加且定位于活化的星胶细胞，在星胶上调CIP2A可导致其增殖活化，分泌损伤因子且导致共培养的神经元突触退变。基于以上背景，我们提出AD脑中CIP2A通过导致星胶A1型活化介导突触损伤。本研究在细胞水平通过在原代星形胶质细胞过表达CIP2A发现在上调CIP2A表达后可导致星胶活化，产生释放细胞因子和Aβ增加，其条件培养基导致神经元发生突触退变；在小鼠整体脑内星形胶质细胞特异性过表达CIP2A导致小鼠出现AD样认知功能损伤，神经元和突触结构和功能受损，脑内细胞因子和Aβ水平增高；进一步探讨CIP2A上调的分子机制发现ChK1活化激活CIP2A-Stat3信号促进星胶激活，靶向抑制 ChK1可逆转AD细胞模型中的CIP2A上调和星胶异常活化。本研究从细胞和整体水平系统阐明了CIP2A促进星形胶质细胞反应性活化的作用和分子机制, 为早期防治AD提供了新的分子靶点。