E2F1 mediates death of B-amyloid-treated cortical neurons in a manner independent of p53 and dependent on Bax and caspase 3

Although B-amyloid (AB) is suggested to play an important role in Alzheimer 's disease, the mechanisms that control AB-evoked toxicity are unclear. We demonstrated previously that the cell cycle-related cyclin-dependent kinase 4/6/retinoblastoma protein pathway is required for AB-mediated death. Howe ver, the downstream target(s) of this pathway are unknown. We show here tha t neurons lacking E2F1, a transcription factor regulated by the retinoblast oma protein, are significantly protected from death evoked by AB, Moreover, p53 deficiency does not protect neurons from death, indicating that E2F1-m ediated death occurs independently of p53. Neurons protected by E2F1 defici ency have reduced Bax-dependent caspase 3-like activity. However, protectio n afforded by E2F1, Bax, or caspase 3 deficiency is transient. In the case of E2F1, but not with Bax or caspase 3 deficiency, delayed death is accompa nied by DEVD-AFC cleavage activity. Taken together, these results demonstra te the required role of E2F1, Bax, and caspase 3 in AB evoked death, but al so suggest the participation of elements independent of these apoptosis reg ulators.