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

Meng Dongli; Mahaman Yacoubou Abdoul Razak; Huang Fang; Wang Zhuoqun; Wang Xiaochuan; Zhang Huiliang; Shentu Yangping; Jiang Nan; Hu Wenting; Westermarck Jukka; Liu Rong; Wang Shiyi; Xiong Jing; Lu Youming; Wang Jianzhi; Zhou Ying

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

Meng Dongli
Mahaman Yacoubou Abdoul Razak
Huang Fang
Wang Zhuoqun
Wang Xiaochuan
Zhang Huiliang
Shentu Yangping
Jiang Nan
Hu Wenting
Westermarck Jukka
Liu Rong
Wang Shiyi
Xiong Jing
Lu Youming
Wang Jianzhi
Zhou Ying
Katso/Avaa
Hu2022_Article_Chk1InhibitionAmelioratesAlzhe.pdf (12.47Mb)
Lataukset: 

Springer
doi:10.1007/s13311-022-01204-z
URI
https://link.springer.com/article/10.1007/s13311-022-01204-z
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2022081154144
Tiivistelmä
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 A beta 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 A beta 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.
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