P3–229: P130, a regulator of the G1 phase of the cell cycle, in Alzheimer disease: Evidence of a stuttered cell cycle

A number of recent findings support the notion of mechanistic parallels between Alzheimer disease and oncogenic processes. Specifically, that neurons in Alzheimer disease, like cancer cells, display aberrant mitotic cell cycle re-entry and apoptotic avoidance. Nonetheless, one clear distinction is that, rather than proliferation, cell cycle dysfunction in AD contributes to neuronal dysfunction and cell death. As such we hypothesized that such neuronal death was likely a consequence of an incomplete or stuttered cell division process. To test this notion we undertook a study of the retinoblastoma-related protein p130, a transcription factor that complexes with E2F4 and, upon phosphorylation, releases E2F4 to promote transcription of genes that repress cell cycle progression from the G1 phase to the S phase. Our results show that there are increases in p130 localized to intraneuronal neurofibrillary tangles and neuritic senile plaques in susceptible hippocampal and cortical neurons in AD. By marked contrast, p130 is found at background levels in these same neuronal populations in nondiseased, age-matched controls. Our data not only provide another line of evidence indicative of cell cycle abnormalities in neurons in Alzheimer disease but also lend further credence to the hypothesis that susceptible neurons fail to complete the cell cycle before they die. Therefore, therapeutics targeted towards initiators of the cell cycle are likely to prove of great efficacy for the treatment of Alzheimer disease. Work in the authors’ laboratories is supported by the Alzheimer’s Association, the National Institutes of Health, Philip Morris USA Inc. and Philip Morris International.