Mitotic signaling by beta-amyloid causes neuronal death

Aggregates of beta-amyloid peptide (beta AP), the main constituent of amylo id plaques in Alzheimer's brain, kill neurons by a not yet defined mechanis m, leading to apoptotic death, Here, we report that both full-length beta A P((1-40)) or ((1-42)) and its active fragment beta AP((25-35)) act as proli ferative 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. Ina ctivation of cyclin-dependent protein kinase-4 or -2 prevented both the ent ry into S phase and the development of apoptosis in beta AP((25-35))-treate d neurons. We conclude that neurons must cross the G1/S transition before s uccumbing to PAP signaling, and therefore multiple steps within this pathwa y may be targets for neuroprotective agents.