P53-mediated G 1/S checkpoint dysfunction in lymphocytes from Alzheimer's disease patients

Abstract

To date, Alzheimer disease (AD) is still difficult to be diagnosed in its earliest stage. The cell cycle aberrations may be the earliest neuropathological events detected in AD thus far. The cell cycle regulatory failure in AD occurring at “G 1/S transition checkpoint” which is mediated by the tumor suppressor protein p53 has been identified. Herein, we observed the response of activated lymphocytes to G 1/S transition blocker to assess the G 1/S checkpoint function and the p53 conformation state adopted in lymphocytes from AD patients and healthy non-AD controls. We found that the activated lymphocytes from AD patients were less sensitive to G 1/S transition blocker than those from controls, indicating that the G 1/S checkpoint failed to function well in AD lymphocytes. In addition, AD cells specifically expressed an anomalous conformationally mutant-like p53 that made these cells distinct from lymphocytes of controls. We speculated that the altered conformational p53 probably be responsible for G 1/S checkpoint dysfunction in AD cells. Our hypothesis was supported by the results that G 1/S checkpoint dysfunction was not restricted to neurons in AD patients, but also occurred in peripheral lymphocytes. Two potential biomarkers were indicated in blood lymphocytes from AD patients: the G 1/S checkpoint dysfunction and the conformationally mutant-like p53 protein.