Amyloid beta 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-alpha 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 beta binds p75(NTR), and that this binding leads to apoptotic cell death. We now report that amyloid beta 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 beta 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 beta to induce receptor activation, and support the hypothesis that p75(NTR) activation by amyloid beta is causally related to Alzheimer's disease.
Yaar
Mina
M
Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Zhai
Sen
S
Fine
Richard E
RE
Eisenhauer
Patricia B
PB
Arble
Bennett L
BL
Stewart
Kenneth B
KB
Gilchrest
Barbara A
BA
D016475:3T3 Cells; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006801:Humans; D008024:Ligands; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry*; D015398:Signal Transduction; D013379:Substrate Specificity; D015854:Up-Regulation
D016229:Amyloid beta-Peptides; D008024:Ligands; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D012313:RNA