Amyloid β Binds Trimers as Well as Monomers of the 75-kDa Neurotrophin Receptor and Activates Receptor Signaling

p75 NTR , a nerve growth factor co-receptor that has been implicated in apoptosis of neurons, is structurally related to Fas and the receptors for tumor necrosis factor-α that display ligand independent assembly into trimers. Using embryonic day 17 fetal rat cortical neurons and p75 NTR -expressing NIH-3T3 cells, we now show that p75 NTR exists as a trimer as well as a monomer. Furthermore, we have reported and others have confirmed that amyloid β binds p75 NTR , and that this binding leads to apoptotic cell death. We now report that amyloid β binds to trimers of p75 NTR as well as to p75 NTR monomers but not to the p140 trkA , the nerve growth factor co-receptor that mediates neuronal survival. Furthermore, amyloid β activates p75 NTR , strongly inducing the transcription of c-Jun mRNA and stimulating the stress-activated c-Jun NH 2 -terminal kinase, as measured by phosphorylation of its substrate (glutathione S -transferase-c-Jun-(1–79)). Our data suggest that p75 NTR may be present as a preformed trimer that binds amyloid β to induce receptor activation, and support the hypothesis that p75 NTR activation by amyloid β is causally related to Alzheimer's disease.