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  3. Chk1 Inhibition Ameliorates Alzheimer's Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling

Chk1 Inhibition Ameliorates Alzheimer's Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling

  • Neurotherapeutics. 2022 Mar;19(2):570-591. doi: 10.1007/s13311-022-01204-z.
Wenting Hu  # 1,  Zhuoqun Wang  # 1,  Huiliang Zhang 1,  Yacoubou Abdoul Razak Mahaman 1 2,  Fang Huang 1,  Dongli Meng 1,  Ying Zhou 3,  Shiyi Wang 4,  Nan Jiang 5,  Jing Xiong 6,  Jukka Westermarck 7 8,  Youming Lu 9,  Jianzhi Wang 1,  Xiaochuan Wang 10,  Yangping Shentu 11,  Rong Liu 12 13
Affiliations

Affiliations

  • 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.
  • 10 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. wxch@mails.tjmu.edu.cn.
  • 11 Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. styp@wmu.edu.cn.
  • 12 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. rong.liu@hust.edu.cn.
  • 13 Collaborative Innovation Center for Brain Science, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China. rong.liu@hust.edu.cn.
  • # Contributed equally.
PMID: 35286657 DOI: 10.1007/s13311-022-01204-z
Abstract

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.

Keywords

APP; Alzheimer’s disease; CIP2A; Chk1; Hyperphosphorylation; PP2A; Tau.

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