@article{6d34ebe2156f460d97181bc1341345e9,
title = "CDT2-controlled cell cycle reentry regulates the pathogenesis of Alzheimer's disease",
abstract = "Introduction: Altered cell cycle reentry has been observed in Alzheimer's disease (AD). Denticleless (DTL) was predicted as the top driver of a cell cycle subnetwork associated with AD. Methods: We systematically investigated DTL expression in AD and studied the molecular, cellular, and behavioral endophenotypes triggered by DTL overexpression. Results: We experimentally validated that CDT2, the protein encoded by DTL, activated cyclin-dependent kinases through downregulating P21, which induced tau hyperphosphorylation and Aβ toxicity, two hallmarks of AD. We demonstrated that cyclin-dependent kinases inhibition by roscovitine not only rescued CDT2-induced cognitive defects but also reversed expression changes induced by DTL overexpression. RNA-seq data from the DTL overexpression experiments revealed the molecular mechanisms underlying CDT2 controlled cell cycle reentry in AD. Discussion: These findings provide new insights into the molecular mechanisms of AD pathogenesis and thus pave a way for developing novel therapeutics for AD by targeting AD specific cell cycle networks and drivers.",
keywords = "Alzheimer's disease, CDK, CDT2, Cell cycle reentry, DTL",
author = "Fang Huang and Minghui Wang and Rong Liu and Wang, {Jian Zhi} and Eric Schadt and Vahram Haroutunian and Pavel Katsel and Bin Zhang and Xiaochuan Wang",
note = "Funding Information: Funding: This work was supported in parts by grants from National Natural Science Foundation of China ( 31528010 , 81571255 , and 31771114 ), grant from Innovative Research Groups of the National Natural Science Foundation of China ( 81721005 ), grant from the Ministry of Science and Technology of China ( 2016YFC1305800 ), the Academic Frontier Youth Team Project to X.W. from Huazhong University of Science and Technology , and grants from the National Institutes of Health / National Institute on Aging ( R01AG046170 , RF1AG054014 , RF1AG057440 , R01AG057907 , HHSN271201300031 ). Funding Information: Funding: This work was supported in parts by grants from National Natural Science Foundation of China (31528010, 81571255, and 31771114), grant from Innovative Research Groups of the National Natural Science Foundation of China (81721005), grant from the Ministry of Science and Technology of China (2016YFC1305800), the Academic Frontier Youth Team Project to X.W. from Huazhong University of Science and Technology, and grants from the National Institutes of Health/National Institute on Aging (R01AG046170, RF1AG054014, RF1AG057440, R01AG057907, HHSN271201300031). Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2019",
month = feb,
doi = "10.1016/j.jalz.2018.08.013",
language = "English",
volume = "15",
pages = "217--231",
journal = "Alzheimer's and Dementia",
issn = "1552-5260",
publisher = "John Wiley & Sons Inc.",
number = "2",
}