Inappropriate cell cycle control is emerging as an important component in the pathogenesis leading to neurodegenerative diseases such as Alzheimer disease (AD), Parkinson disease (PD) and frontotemporal dementia (FTD). We and others have shown expression of cell cycle-related proteins in the vulnerable neurons in these neurodegenerative diseases, and that DNA replication is occurring gin these cells provides compelling evidence that this represents a bona fide mitotic event. Importantly, the earlier occurrence of cell cycle events compared to other pathologies including tau phosphorylation and neurofibrillary tangles (NFT) in AD suggests that a mitotic cell cycle-related mechanism may not only play a role in AD but also in other tauopathies such as FTD. Additional supportive evidence for an important role for cell cycle events in tauopathy diseases derives from transgenic animal models. First, cell cycle related changes are evident in animal model of FTD. Second, we recently developed a dedicated transgenic model (CaMKII-MYC) of neuron-specific cell cycle re-entry driven by an inducible MYC oncogene in forebrain neurons. Analysis of such animals shows that MYC expression results in cell cycle re-entry leading to tau phosphorylation, neurodegeneration, and cognitive deficits. The observations from these transgenic lines pinpoint aberrant cell cycle control as an early and perhaps pivotal factor in the pathogenesis of tauopathy. We propose to test this notion by inhibiting cell cycle re-entry in both JNPL3, a transgenic mouse model for FTD, and CaMKII-MYC transgenic models. Using roscovitine and flavopiridol to block cell cycle re-entry, we will assess the role of cell cycle re-entry in the pathology (including neuronal degeneration, tau phosphorylation) and behavioral deficits including cognitive and motor functions observed in these mice. At the conclusion of these studies, it is anticipated that we will not only realize the role of cell cycle-mediated events in relation to other aspects of disease pathogenesis but also the potential utility of using cell cycle inhibitory approaches as a therapeutic regimen in FTD.