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Objective: Selective neuronal vulnerability in neurodegenerative diseases is poorly understood. In Alzheimer's disease, the basal forebrain cholinergic neurons are selectively vulnerable, putatively because of their expression of the cell death mediator p75(NTR) (the common neurotrophin receptor), and its interaction with proapoptotic ligands pro-nerve growth factor and amyloid-beta peptide. However, the relation between amyloid precursor protein (APP) and p75(NTR) has not been described previously., Methods: APP and p75(NTR) were assayed for interaction by coimmunoprecipitation in vitro and in vivo, yeast two-hybrid assay, bioluminescence resonance energy transfer, and confocal microscopy. Effects on APP processing and signaling were studied using immunoblotting, enzyme-linked immunosorbent assays, and luciferase reporter assays., Results: The results of this study are as follows: (1) p75(NTR) and APP interact directly; (2) this interaction is modified by ligands nerve growth factor and beta-amyloid; (3) APP and p75(NTR) colocalization in vivo is modified in Alzheimer's model transgenic mice; (4) APP processing is altered by p75(NTR), and to a lesser extent, p75(NTR) processing is altered by the presence of APP; (5) APP-dependent transcription mediated by Fe65 is blocked by p75(NTR); and (6) coexpression of APP and p75(NTR) triggers cell death., Interpretation: These results provide new insight into the emerging signaling network that mediates the Alzheimer's phenotype and into the mechanism of basal forebrain cholinergic neuronal selective vulnerability. In addition, the results argue that the interaction between APP and p75(NTR) may represent a therapeutic target in Alzheimer's disease.

The common neurotrophin receptor p75(NTR) remains one of the most enigmatic of the tumor necrosis factor receptor (TNFR) superfamily: on the one hand, it displays a death domain and has been shown to be capable of mediating programmed cell death (PCD) upon ligand binding; on the other hand, its death domain is of type II (unlike that of Fas or TNFR I), and it has also been shown to be capable of mediating cell death in response to the withdrawal of ligand. Thus, p75(NTR) may function as a death receptor-similar to Fas or TNFR I-or a dependence receptor-similar to deleted in colorectal cancer (DCC) or uncoordinated gene-5 homologues 1-3 (UNC5H1-3). Here, we review the data relating to the mediation of PCD by p75(NTR), and suggest that one reasonable model for the apparently paradoxical effects of p75(NTR) is that this receptor functions as a "quality control" in that it is capable of mediating PCD in at least four situations: (1). withdrawal of neurotrophins; (2). exposure to mismatched neurotrophins; (3). exposure to unprocessed neurotrophins; and (4). exposure of inappropriately immature cells to neurotrophins. Results to date suggest that these functions are mediated through different underlying mechanisms, and that their respective signaling pathways are cell type and co-receptor dependent.

The biochemical mechanism by which neurons become dependent on neurotrophins for survival is unknown. We found previously that the common neurotrophin receptor, p75(NTR), is a mediator of neurotrophin dependence and that this effect requires a novel type of domain dubbed a neurotrophin dependence domain. We report here that, in contrast to other proapoptotic receptors such as Fas, apoptosis induction by p75(NTR) requires monomerization, with dimerization inhibiting the effect. Blocking the proapoptotic effect of the monomer by dimerization requires a distinct domain that lies at the carboxyterminus of p75(NTR). These results define a novel type of domain required for inhibiting apoptosis induction by p75(NTR)., (Copyright 2000 Wiley-Liss, Inc.)

During development, neurons pass through a critical phase in which survival is dependent on neurotrophin support. In order to dissect the potential role of p75NTR, the common neurotrophin receptor, in neurotrophin dependence, we expressed wild-type and mutant p75NTR in cells that do not express endogenous p75NTR or Trk family members (NIH3T3). Expression of wild-type p75NTR created a state of neurotrophin dependence: cells could be rescued by nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), or neurotrophin-3 (NT-3), but not by a mutant NGF that binds well to Trk A but poorly to p75NTR. Similarly, expression of p75NTR in human prostate cancer cells in culture rendered a metastatic tumor cell line (PC-3) sensitive to the availability of neurotrophins for survival. Moreover, expression of mutant p75NTR's in another neurotrophin-insensitive cell line (HEK293T) showed that a domain within the intracellular domain governs alternate responses to neurotrophins: the carboxy terminus of the intracellular domain of p75NTR including the sixth alpha helix domain is necessary for rescue by BDNF, but not NGF. These results, when considered with previous studies of the timing of p75NTR expression, support the hypothesis that p75NTR is a mediator of neurotrophin dependence during the critical phase of developmental cell death and during the progression of carcinogenesis in prostate cancer.

The common neurotrophin receptor, p75(NTR), has been shown to signal in the absence of Trk tyrosine kinase receptors, including induction of neural apoptosis and activation of NF-kappaB. However, the mechanisms by which p75(NTR) initiates these intracellular signal transduction pathways are unknown. Here we report interactions between p75(NTR) and the six members of TRAF (tumor necrosis factor receptor-associated factors) family proteins. The binding of different TRAF proteins to p75(NTR) was mapped to distinct regions in p75(NTR). Furthermore, TRAF4 interacted with dimeric p75(NTR), whereas TRAF2 interacted preferentially with monomeric p75(NTR). TRAF2-p75(NTR), TRAF4-p75(NTR), and TRAF6-p75(NTR) interactions modulated p75(NTR)-induced cell death and NF-kappaB activation with contrasting effects. Coexpression of TRAF2 with p75(NTR) enhanced cell death, whereas coexpression of TRAF6 was cytoprotective. Furthermore, overexpression of TRAF4 abrogated the ability of dimerization to prevent the induction of apoptosis normally mediated by monomeric p75(NTR). TRAF4 also inhibited the NF-kappaB response, whereas TRAF2 and TRAF6 enhanced p75(NTR)-induced NF-kappaB activation. These results demonstrate that TRAF family proteins interact with p75(NTR) and differentially modulate its NF-kappaB activation and cell death induction.

Cells depend on specific stimuli, such as trophic factors, for survival and in the absence of such stimuli, undergo apoptosis. How do cells initiate apoptosis in response to the withdrawal of trophic factors or other dependent stimuli? Recent studies of apoptosis induction by neurotrophin withdrawal argue for a novel form of pro-apoptotic signal transduction - 'negative signal transduction' - in which the absence of ligand-receptor interaction induces cell death. We have found that the prototype for this form of signaling - the common neurotrophin receptor, p75NTR - creates a state of cellular dependence (or addiction) on neurotrophins, and that this effect requires an 'addiction/dependence domain' (ADD) in the intracytoplasmic region of p75NTR. We have recently found other receptors that include dependence domains, arguing that dependence receptors, and their associated dependence domains, may be involved in a rather general mechanism to create cellular states of dependence on trophic factors, cytokines, adhesion, electrical activity and other dependent stimuli.

The neurotrophin receptor (NTR) and tumor necrosis factor receptor family of receptors regulate apoptotic cell death during development and in adult tissues [Beutler and van Huffel, Science 264 (1994) 667-668]. We have examined a fragment of p75NTR from the carboxyl terminus of the receptor and a variant form of this peptide via NMR techniques and in vitro assays for apoptotic activity. The wild type peptide induces apoptosis and adopts a helical conformation oriented parallel to the surface of lipid micelles, whereas the variant form adopts a non-helical conformation in the presence of lipid and shows no activity. These experiments suggest a link between structure and function of the two peptides.

The ongoing dissection of the roles of p75NTR and TrkA, -B and -C in neurotrophin signaling has generated a number of apparent paradoxes. Limiting consideration to the role of p75NTR in cell death, a theory is proposed that is based on the following postulates: (1) that p75NTR displays a pro-apoptotic intrinsic (ligand-independent, Trk-independent) receptor effect (IRE), which is inhibited by ligand binding; (2) that p75NTR and TrkA exhibit mutual repression of signaling; and (3) that p75NTR and TrkA are required for the efficient generation of high-affinity NGF binding sites.

The low-affinity nerve growth factor receptor (NGFR) p75NGFR induces apoptosis in the absence of nerve growth factor (NGF) binding but enhances neural survival when bound by NGF. Basal forebrain cholinergic neurons express the highest levels of p75NGFR in the adult human brain and are preferentially involved in Alzheimer disease, raising the question of whether there may be a functional relationship between the expression of p75NGFR and basal forebrain cholinergic neuronal degeneration in Alzheimer disease. The expression of p75NGFR by wild-type and mutant PC12 cells potentiated cell death induced by beta-amyloid peptide. NGF binding to p75NGFR inhibited the toxicity of beta-amyloid peptide, whereas NGF binding to TrkA, the high-affinity NGFR, enhanced it. These results suggest a possible link between beta-amyloid peptide toxicity and preferential degeneration of cells expressing p75NGFR.

The tumor necrosis factor receptor superfamily includes twelve members, at least two of which--tumor necrosis factor receptor I and FAS/Apo-1--induce cell death following ligand binding. This review summarizes data suggesting that two other members of the family--p75NGFR and CD40--achieve a similar effect in the inverse fashion; they induce apoptosis constitutively when unbound by their respective ligands, with the induction of apoptosis being inhibited by the binding of their respective ligands. The potential roles that such receptors may play in development and pathological processes are discussed.

Nerve growth factor (NGF) binding to cellular receptors is required for the survival of some neural cells. In contrast to TrkA, the high-affinity NGF receptor that transduces NGF signals for survival and differentiation, the function of the low-affinity NGF receptor, p75NGFR, remains uncertain. Expression of p75NGFR induced neural cell death constitutively when p75NGFR was unbound; binding by NGF or monoclonal antibody, however, inhibited cell death induced by p75NGFR. Thus, expression of p75NGFR may explain the dependence of some neural cells on NGF for survival. These findings also suggest that p75NGFR has some functional similarities to other members of a superfamily of receptors that include tumor necrosis factor receptors, Fas (Apo-1), and CD40.