Characterization of the signaling pathway downstream p75 neurotrophin receptor involved in β-amyloid peptide-dependent cell death

The accumulation of beta-amyloid (A beta) peptide is a key pathogenic event in Alzheimer's disease. Previous studies have shown that A beta peptide can damage neurons by activating the p75 neurotrophin receptor (p75(NTR)). However, the signaling pathway leading to neuronal cell death is not completely understood. By using a neuroblastoma cell line devoid of neurotrophin receptors and engineered to express either a full-length or a death domain (DD)-truncated form of p75(NTR), we demonstrated that A beta peptide activates the mitogen-activated protein kinases (MAPKs) p38 and c-jun N-terminal kinase (JNK). We also found thatA peptide induces the translocation of nuclear factor-kappa B (NF-kappa B). These events depend on the DD of p75(NTR). beta-Amyloid (A beta) peptide was found not to be toxic when the above interactors were inhibited, indicating that they are required for A beta-induced neuronal cell death. p75 neurotrophin receptor (p75(NTR))-expressing cells became resistant to A beta toxicity when transfected with dominant-negative mutants of MAPK kinases 3,4, or 6 (MKK3, MKK4, orMKK6), the inhibitor of kappa B alpha, or when treated with chemical inhibitors of p38 and JNK. Furthermore, p75(NTR)-expressing cells became resistant to A beta peptide upon transfection with a dominant-negative mutant of p53. These results were obtained in the presence of normal p38 and JNK activation, indicating that p53 acts downstream of p38 and JNK. Finally, we demonstrated that NF-kappa B activation is dependent on p38 and JNK activation. Therefore, our data Suggest a signaling pathway in which A beta peptide binds to p75(NTR) and activates p38 and JNK in a DD-dependent manner, followed by NF-kappa B translocation and p53 activation.