Mitotic signaling by β-amyloid causes neuronal death

Aggregates of beta-amyloid peptide (beta AP), 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 beta AP((1-40)) or ((1-42)) and its active fragment beta AP((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 beta AP((25-35))-treated neurons. We conclude that neurons must cross the G1/S transition before succumbing to PAP signaling, and therefore multiple steps within this pathway may be targets for neuroprotective agents.