Cell Cycle Inhibitors in Alzheimer Disease

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DESCRIPTION (provided by applicant): Inappropriate cell cycle control is emerging as an important component in the pathogenesis leading to Alzheimer disease (AD). We and others have shown expression of cell cycle-related proteins in the vulnerable neurons in AD. Evidence that this represents a bona fide mitotic event is proved by the observation that DNA replication is occurring in these cells. The earlier occurrence of cell cycle events compared to other pathologies suggests that a mitotic cell cycle-related mechanism may play a role in AD. Additional supportive evidence for an important role for cell cycle events in disease derives from transgenic animal models. First, in transgenic lines with a high amyloid burden, such as Tg2576, there are increases in cell cycle proteins and chromosome duplication and such changes predate frank amyloid-2 deposition. Second, we recently developed a dedicated transgenic model (CaMKII-MYC) of neuron-specific inducible oncogene driven cell cycle that specifically expresses myc in forebrain neurons. Analysis of such animals shows that MYC expression results in cell cycle re-entry leading to tau phosphorylation, intraneuronal accumulation of amyloid-b, neurodegeneration, and cognitive deficits. The observations from these transgenic lines pinpoint abberant cell cycle control as an early and perhaps pivotal factor in the pathogenesis of AD. We propose to test this notion by inhibiting cell cycle re-entry in both Tg2576 and CaMKII-MYC transgenic models. Using roscovitine to block cell cycle re-entry, we will assess the role of cell cycle re-entry in the pathology (including neuronal degeneration, tau phosphorylation, amyloid-b) and behavioral deficits (such as Morris Water Maze) observed in these mice. At this 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 AD.