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.
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.