Dataset Information
CDT2-controlled cell cycle reentry regulates the pathogenesis of Alzheimer's disease.
Ontology highlight
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.
SUBMITTER: Huang F
PROVIDER: S-EPMC6758558 | biostudies-literature | 2019 Feb
REPOSITORIES: biostudies-literature
Publications
CDT2-controlled cell cycle reentry regulates the pathogenesis of Alzheimer's disease.
Alzheimer's & dementia : the journal of the Alzheimer's Association 20181012 2
<h4>Introduction</h4>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.<h4>Methods</h4>We systematically investigated DTL expression in AD and studied the molecular, cellular, and behavioral endophenotypes triggered by DTL overexpression.<h4>Results</h4>We experimentally validated that CDT2, the protein encoded by DTL, activated cyclin-dependent kinases through downregulating ...[more]