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

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-ind...

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Autores principales: Hu, Wenting, Wang, Zhuoqun, Zhang, Huiliang, Mahaman, Yacoubou Abdoul Razak, Huang, Fang, Meng, Dongli, Zhou, Ying, Wang, Shiyi, Jiang, Nan, Xiong, Jing, Westermarck, Jukka, Lu, Youming, Wang, Jianzhi, Wang, Xiaochuan, Shentu, Yangping, Liu, Rong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9226264/
https://www.ncbi.nlm.nih.gov/pubmed/35286657
http://dx.doi.org/10.1007/s13311-022-01204-z
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author Hu, Wenting
Wang, Zhuoqun
Zhang, Huiliang
Mahaman, Yacoubou Abdoul Razak
Huang, Fang
Meng, Dongli
Zhou, Ying
Wang, Shiyi
Jiang, Nan
Xiong, Jing
Westermarck, Jukka
Lu, Youming
Wang, Jianzhi
Wang, Xiaochuan
Shentu, Yangping
Liu, Rong
author_facet Hu, Wenting
Wang, Zhuoqun
Zhang, Huiliang
Mahaman, Yacoubou Abdoul Razak
Huang, Fang
Meng, Dongli
Zhou, Ying
Wang, Shiyi
Jiang, Nan
Xiong, Jing
Westermarck, Jukka
Lu, Youming
Wang, Jianzhi
Wang, Xiaochuan
Shentu, Yangping
Liu, Rong
author_sort Hu, Wenting
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01204-z.
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spelling pubmed-92262642022-06-25 Chk1 Inhibition Ameliorates Alzheimer’s Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling Hu, Wenting Wang, Zhuoqun Zhang, Huiliang Mahaman, Yacoubou Abdoul Razak Huang, Fang Meng, Dongli Zhou, Ying Wang, Shiyi Jiang, Nan Xiong, Jing Westermarck, Jukka Lu, Youming Wang, Jianzhi Wang, Xiaochuan Shentu, Yangping Liu, Rong Neurotherapeutics Original Article 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01204-z. Springer International Publishing 2022-03-14 2022-03 /pmc/articles/PMC9226264/ /pubmed/35286657 http://dx.doi.org/10.1007/s13311-022-01204-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Hu, Wenting
Wang, Zhuoqun
Zhang, Huiliang
Mahaman, Yacoubou Abdoul Razak
Huang, Fang
Meng, Dongli
Zhou, Ying
Wang, Shiyi
Jiang, Nan
Xiong, Jing
Westermarck, Jukka
Lu, Youming
Wang, Jianzhi
Wang, Xiaochuan
Shentu, Yangping
Liu, Rong
Chk1 Inhibition Ameliorates Alzheimer’s Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling
title Chk1 Inhibition Ameliorates Alzheimer’s Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling
title_full Chk1 Inhibition Ameliorates Alzheimer’s Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling
title_fullStr Chk1 Inhibition Ameliorates Alzheimer’s Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling
title_full_unstemmed Chk1 Inhibition Ameliorates Alzheimer’s Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling
title_short Chk1 Inhibition Ameliorates Alzheimer’s Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling
title_sort chk1 inhibition ameliorates alzheimer’s disease pathogenesis and cognitive dysfunction through cip2a/pp2a signaling
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9226264/
https://www.ncbi.nlm.nih.gov/pubmed/35286657
http://dx.doi.org/10.1007/s13311-022-01204-z
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