Chk1 Inhibition Ameliorates Alzheimers Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling

doi:10.1007/s13311-022-01204-z

科研成果详情

题名	Chk1 Inhibition Ameliorates Alzheimers Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling
作者	Hu, Wenting 1; Wang, Zhuoqun 1; Zhang, Huiliang 1; Mahaman, Yacoubou Abdoul Razak 1,2; Huang, Fang 1; Meng, Dongli 1; Zhou, Ying 3; Wang, Shiyi 4; Jiang, Nan 5; Xiong, Jing 6; Westermarck, Jukka 7,8; Lu, Youming 9; Wang, Jianzhi 1; Wang, Xiaochuan 1; Shentu, Yangping 5; Liu, Rong 1,9
发表日期	2022-03
发表期刊	Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 影响因子和分区
语种	英语
原始文献类型	Article
关键词	APP Alzheimer’s disease CIP2A Chk1 Hyperphosphorylation PP2A Tau.
其他关键词	PROTEIN PHOSPHATASE 2A ; CELL-CYCLE ; OXIDATIVE STRESS ; STRAND BREAKS ; CHECKPOINT ; KINASE ; TAU ; PHOSPHORYLATION ; PF-00477736 ; THERAPY
摘要	Alzheimer's disease (AD) is the most common neurodegenerative disease with limited therapeutic strategies. Cell cycle checkpoint protein kinase 1 (Chk1) is a Ser/Thr protein kinase which is activated in response to DNA damage, the latter which is an early event in AD. However, whether DNA damage-induced Chk1 activation participates in the development of AD and Chk1 inhibition ameliorates AD-like pathogenesis remain unclarified. Here, we demonstrate that Chk1 activity and the levels of protein phosphatase 2A (PP2A) inhibitory protein CIP2A are elevated in AD human brains, APP/PS1 transgenic mice, and primary neurons with Aβ treatment. Chk1 overexpression induces CIP2A upregulation, PP2A inhibition, tau and APP hyperphosphorylation, synaptic impairments, and cognitive memory deficit in mice. Moreover, Chk1 inhibitor (GDC0575) effectively increases PP2A activity, decreases tau phosphorylation, and inhibits Aβ overproduction in AD cell models. GDC0575 also reverses AD-like cognitive deficits and prevents neuron loss and synaptic impairments in APP/PS1 mice. In conclusion, our study uncovers a mechanism by which DNA damage-induced Chk1 activation promotes CIP2A-mediated tau and APP hyperphosphorylation and cognitive dysfunction in Alzheimer's disease and highlights the therapeutic potential of Chk1 inhibitors in AD.
资助项目	National Natural Science Foundation of China[31970964];
出版者	SPRINGER
出版地	NEW YORK
ISSN	1878-7479
EISSN	1878-7479
卷号	19 期号:2 页码:570-591
DOI	10.1007/s13311-022-01204-z
页数	22
WOS类目	Clinical Neurology ; Neurosciences ; Pharmacology & Pharmacy
WOS研究方向	Neurosciences & Neurology ; Pharmacology & Pharmacy
WOS记录号	WOS:000776031100002
收录类别	PUBMED ; SCOPUS ; SCIE
URL	查看原文
PubMed ID	35286657
SCOPUSEID	2-s2.0-85126232705
通讯作者地址	[Wang, Xiaochuan]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 ; [Liu, Rong]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 ; [Shentu, Yangping]Department of Pathology,The First Affiliated Hospital of Wenzhou Medical University,Wenzhou,China
Scopus学科分类	Pharmacology;Neurology (clinical);Pharmacology (medical)
引用统计	被引频次：3[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/55425
专题	附属第一医院_肾内科基础医学院（机能实验教学中心）_病理学与病理生理学系
通讯作者	Wang, Xiaochuan; Shentu, Yangping; Liu, Rong
作者单位	1.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; 2.Cognitive Impairment Ward of Neurology Department,The Third Affiliated Hospital of Shenzhen University,Shenzhen,China; 3.Department of Nephrology,The First Affiliated Hospital of Wenzhou Medical University,Wenzhou,China; 4.Wenzhou Medical University,Wenzhou,China; 5.Department of Pathology,The First Affiliated Hospital of Wenzhou Medical University,Wenzhou,China; 6.Department of Nephrology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China; 7.Turku Centre for Biotechnology,University of Turku and Abo Akademi University,Turku,Finland; 8.Institute of Biomedicine,University of Turku,Turku,Finland; 9.Collaborative Innovation Center for Brain Science,The Institute of Brain Research,Huazhong University of Science and Technology,Wuhan,China
通讯作者单位	附属第一医院; 第一临床医学院（信息与工程学院）、附属第一医院
推荐引用方式 GB/T 7714	Hu, Wenting,Wang, Zhuoqun,Zhang, Huiliang,et al. Chk1 Inhibition Ameliorates Alzheimers Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling[J]. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics,2022,19(2):570-591.
APA	Hu, Wenting., Wang, Zhuoqun., Zhang, Huiliang., Mahaman, Yacoubou Abdoul Razak., Huang, Fang., ... & Liu, Rong. (2022). Chk1 Inhibition Ameliorates Alzheimers Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 19(2), 570-591.
MLA	Hu, Wenting,et al."Chk1 Inhibition Ameliorates Alzheimers Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling".Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 19.2(2022):570-591.