Abstract
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.
Highlights
Bers of this superfamily, may induce cellular apoptosis
The level of p140trkA, the receptor that in coordination with p75NTR appears to mediate the beneficial effects of NGF [2], is decreased in the human brain of Alzheimer’s disease (AD) patients (16 –19), whereas p75NTR levels are not [20, 21], suggesting that AD may result in part from a relative overexpression of p75NTR that renders neurons more susceptible to A-induced apoptosis [22]
Ceramide generation is accompanied by activation of the Jun amino-terminal kinase (JNK) [7], allowing this family of kinases to phosphorylate and activate c-Jun and other transcription factors [23]
Summary
Vol 277, No 10, Issue of March 8, pp. 7720 –7725, 2002 Printed in U.S.A. Amyloid  Binds Trimers as Well as Monomers of the 75-kDa Neurotrophin Receptor and Activates Receptor Signaling*. It is still not clear whether up-regulation of NFB through p75NTR [25] occurs independently of the apoptotic pathway and suppresses cell death signals, as is the case with the TNF-␣ receptor [26], or whether NFB and JNK activation are part of the same signaling pathway leading to apoptosis, as suggested by Kuner et al [9] Other receptors of this superfamily, in particular TNF-␣ receptors and Fas, were recently found to be present both as preformed transmembrane trimeric complexes and as individual monomeric receptors [27, 28], with apoptotic signaling initiated only when a ligand binds the trimeric form of the receptor [27, 28]. We propose that binding of A to p75NTR trimers is a key pathomechanism of AD
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