Mitotic signaling by beta-amyloid peptide causes neuronal death

Aggregates of b-amyloid peptide (bAP), the main constituent of amyloid plaques in Alzheimer’s brain, kill neurons by a not yet defined mechanism, leading to apoptotic death. Here, we report that both full-length bAP(1– 40) or (1– 42) and its active fragment bAP(25–35) act as proliferative signals for differentiated cortical neurons, driving them into the cell cycle. The cycle followed some of the steps observed in proliferating cells, including induction of cyclin D1, phosphorylation of retinoblastoma, and induction of cyclin E and A, but did not progress beyond S phase. Inactivation of cyclin-dependent protein kinase-4 or -2 prevented both the entry into S phase and the development of apoptosis in bAP(25– 35)-treated neurons. We conclude that neurons must cross the G1/S transition before succumbing to bAP signaling, and therefore multiple steps within this pathway may be targets for neuroprotective agents.