Increased p27, an essential component of cell cycle control, in Alzheimer's disease.

A number of recent findings have demonstrated re-expression of cell cycle-related proteins in vulnerable neurones in Alzheimer's disease. We hypothesize that this attempt by neurones to re-enter mitosis is a response to external growth stimuli that leads to an abortive re-entry into the cell cycle and, ultimately, neuronal degeneration. In this study, to further delineate the role of mitotic processes in the pathogenesis of Alzheimer's disease, we investigated p27, a cyclin-dependent kinase inhibitor that plays a negatively regulatory role in cell cycle progression that, once phosphorylated at Thr187, is degraded via an ubiquitin-proteasome pathway. Here we report that both p27 and phosphorylated p27 (Thr187) show increases in the cytoplasm of vulnerable neuronal populations in Alzheimer's disease vs. age-matched control subjects. Importantly, phosphorylated p27 (Thr187) shows considerable overlap with tau-positive neurofibrillary pathology, including neurofibrillary tangles, dystrophic neurites and neuropil threads. The findings presented here suggest that dysregulation of the cell cycle plays a crucial role in the pathogenesis of Alzheimer's disease that may provide a novel mechanistic basis for therapeutic intervention.