Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Biology, Boston University, Boston, USA.
Neurobiol Aging. 2019 Mar;75:198-208. doi: 10.1016/j.neurobiolaging.2018.11.023. Epub 2018 Dec 6.
Reactive astrogliosis and early synaptic degeneration are 2 characteristic hallmarks in Alzheimer's disease (AD) brains, but a direct link between the 2 events has not been established. Here, we show that cancerous inhibitor of PP2A (CIP2A), a cancerous protein with high expression level in astrocytes, is upregulated in patients with AD and 3xTg-AD transgenic mice. Overexpression of CIP2A in astrocytes through adeno-associated virus infection both in cultured cells and in mice brains results in activation of astrocytes, increased production of cytokines and Aβ, and synaptic degeneration indicated by decreased levels of synaptic proteins, spine loss, and impairment in long-term potentiation. As a result of synaptic degeneration, CIP2A overexpression in astrocytes in vivo induces significant deficits in visual episodic memory detected by novel objective recognition test and spatial memory detected by Morris water maze. We conclude that CIP2A-promoted astrogliosis induces synaptic degeneration and cognitive deficits in AD.
反应性星形胶质细胞增生和早期突触变性是阿尔茨海默病（AD）大脑的 2 个特征性标志，但这 2 个事件之间的直接联系尚未确定。在这里，我们表明，在 AD 患者和 3xTg-AD 转基因小鼠中，星形胶质细胞中高表达的致癌性蛋白磷酸酶 2A 抑制剂（CIP2A）上调。通过腺相关病毒感染在培养细胞和小鼠大脑中过表达 CIP2A 会导致星形胶质细胞激活、细胞因子和 Aβ 的产生增加，以及突触蛋白水平降低、棘突丢失和长时程增强受损等突触变性的迹象。由于突触变性，星形胶质细胞中 CIP2A 的过表达在体内导致通过新的客观识别测试检测到的视觉情景记忆和通过 Morris 水迷宫检测到的空间记忆显著缺陷。我们得出结论，CIP2A 促进的星形胶质细胞增生导致 AD 中的突触变性和认知缺陷。
