Amyloid β binds trimers as well as monomers of the 75-kDa neurotrophin receptor and activates receptor signaling

Abstract

p75NTR, 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-a that display ligand independent assembly into trimers. Using embryonic day 17 fetal rat cortical neurons and p75NTR-expressing NIH-3T3 cells, we now show that p75NTR exists as a trimer as well as a monomer. Furthermore, we have reported and others have confirmed that amyloid β binds p75NTR, and that this binding leads to apoptotic cell death. We now report that amyloid β binds to trimers of p75NTR as well as to p75NTR monomers but not to the p140trkA, the nerve growth factor co-receptor that mediates neuronal survival. Furthermore, amyloid β activates p75NTR, strongly inducing the transcription of c-Jun mRNA and stimulating the stress-activated c-Jun NH2-terminal kinase, as measured by phosphorylation of its substrate (glutathione S-transferase-c-Jun-(1-79)). Our data suggest that p75NTR may be present as a preformed trimer that binds amyloid β to induce receptor activation, and support the hypothesis that p75NTR activation by amyloid β is causally related to Alzheimer's disease.