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Keywords:

  • amyloid;
  • apoptosis;
  • c-Jun Kinase;
  • nuclear factor κB;
  • p75 nerve growth factor receptor

Abstract

  1. Top of page
  2. Abstract
  3. Structure of p75NTR
  4. Aβ binds to p75NTR
  5. Aβ-activated p75NTR-mediated signal cascades
  6. Alternative hypotheses of Aβ-p75NTR-mediated signals
  7. References

Alzheimer's disease is characterized by the over-production and accumulation of amyloidogenic Aβ peptide, which can induce cell death in vitro. It has been suggested that the death signal could be transduced by the pan neurotrophin receptor (p75NTR). p75NTR is well known for its ability to mediate neuronal death in neurodegenerative conditions and is inextricably linked with changes that occur in Alzheimer's disease. Moreover, Aβ binds to p75NTR, activating signalling cascades. However, the complexity of p75NTR-mediated signalling, which does not always promote cell death, leaves open the possibly of Aβ promoting death via an alternative signalling pathway or the regulation of other p75NTR-mediated actions. This review focuses on the interactions between Aβ and p75NTR in the context of the broader p75NTR signalling field, and offers alternative explanations for how p75NTR might contribute to the aetiology of Alzheimer's disease.

Abbreviations used

amyloid β peptide

APP

amyloid protein precursor

Bcl-2

B-cell lymphoma/leukemia-2

JNK

c-Jun kinase

NFκB

nuclear factor κB

NGF

nerve growth factor

NRAGE

neurotrophin receptor-interacting MAGE homologue

NRH2

NGF receptor homologue 2

p75NTR

pan neurotrophin receptor

TNFR

tumour necrosis factor receptor

TRAF

TNF receptor-associated factors

TrkA

tropomyosin-receptor-kinase A

Alzheimer's disease, a commonly occurring neurodegenerative condition that affects more than 20 million people world wide, is characterized by progressive dementia and pathological deposits of the amyloidogenic peptide fragment Aβ. Although the long-standing dogma, that accumulation of Aβ, either by increased production or reduced clearance, is causally linked to the disease, has been regularly challenged over the past 20 years, it is still the most widely accepted hypothesis in the field (Walsh and Selkoe 2004). However, the way in which over-production of the amyloidogenic peptide causes dementia remains a hotly debated topic. It has been demonstrated by many research groups that Aβ is neurotoxic, supporting the idea that neuronal loss underlies the mental decline observed in sufferers of Alzheimer's disease. However, the size (40 or 42 amino acids long) and aggregation state of the Aβ peptide required to mediate neuronal degeneration in vivo remains unclear (Morgan et al. 2004).

Alternative hypotheses have also been put forward to explain (at least partially) the aetiology of Alzheimer's disease. One of these has arisen from the demonstrated intricate connection between Alzheimer's disease and the neurotrophin family of growth factors, suggesting a causal link (Rabizadeh et al. 1994). An early indicator of Alzheimer's disease is the degeneration of the cholinergic basal forebrain neurons, which express the highest levels of the pan neurotrophin receptor (p75NTR) in the adult brain (Gibbs et al. 1989). These neurons are dependent on nerve growth factor (NGF)-mediated survival signalling through the tropomyosin-receptor-kinase A (TrkA) neurotrophin receptor which, unlike p75NTR, is reduced in Alzheimer's disease patients. In addition, p75NTR is also expressed in the Trk-negative, degenerating cortical neurons of Alzheimer's disease sufferers, a situation which is not reflected in healthy elderly subjects (Mufson et al. 1992). Furthermore, the neurotrophins, acting differentially through Trk receptors and p75NTR, appear to regulate the expression and cleavage of the amyloid protein precursor (APP; Costantini et al. 2005a), potentially regulating the generation of Aβ with ageing.

Given that up-regulation and ligand activation of p75NTR have been widely shown to mediate neural cell death in animal models of neurodegenerative disease (Coulson et al. 2000a; Dechant and Barde 2002; Roux and Barker 2002), and that the pro-form of NGF, which selectively binds to p75NTR to promote neuronal death (Lee et al. 2001), is increased in Alzheimer's disease (Fahnestock et al. 2001; Peng et al. 2004), the receptor is a strong candidate for independently mediating the degeneration occurring in Alzheimer's disease. Even more tantalizing, however, is the repeated demonstration during the last decade that Aβ is a ligand for p75NTR (see below), providing a possible mechanism through which Aβ neurotoxicity is mediated.

Nonetheless, it should be acknowledged that conflicting lines of evidence also exist: p75NTR expression in mice bearing the Swedish presenilin mutation does not correlate with increased cell death (Jaffar et al. 2001), reduced levels of p75NTR in the basal forebrain neurons correlate with cognitive impairment (Mufson et al. 2002), and human neurons appear to be resistant to Aβ toxicity (Zhang et al. 2003). The signalling pathways of p75NTR are also complicated by the receptor's association with co-receptors and its differing functions, depending on cell type and context (Dechant and Barde 2002). Thus, interpretation of results from the proponents of the Aβ–p75NTR neurotoxicity hypothesis is not easy.

Structure of p75NTR

  1. Top of page
  2. Abstract
  3. Structure of p75NTR
  4. Aβ binds to p75NTR
  5. Aβ-activated p75NTR-mediated signal cascades
  6. Alternative hypotheses of Aβ-p75NTR-mediated signals
  7. References

As the 16th member of the tumour necrosis factor receptor (TNFR) family, p75NTR is structurally characterized by its large cysteine-rich extracellular domain, that forms four ligand-binding pockets (Fig. 1). It is a single pass transmembrane receptor protein and, like APP, is cleaved first extracellularly by a β-secretase metalloprotease, and then within the transmembrane domain by presenilin-dependent γ-secretase activity (Jung et al. 2003; Kanning et al. 2003). Following cleavage, the cytoplasmic intracellular domain translocates to the nucleus and/or is rapidly degraded (Kanning et al. 2003; Geetha et al. 2005). The cytoplasmic domain of p75NTR is characterized by an unstructured, flexible juxtamembrane linker region which includes the death-promoting Chopper domain (amino acids 274–303; Coulson et al. 2000b), and the α-helical TNFR-like death-domain sequence (Liepinsh et al. 1997). Both intracellular domains are capable of promoting independent signalling pathways, but they can also act in synergy. A number of p75NTR-associated proteins bind to either the Chopper domain or the TNFR-like death domain, or to both (Roux and Barker 2002; Coulson et al. 2004; Gentry et al. 2004). Although much of the p75NTR signalling field has focused on those interactions which promote cell death, there are a variety of alternative signalling outcomes, including proliferation, differentiation, and regulation of neurite outgrowth (Dechant and Barde 2002; Roux and Barker 2002).

image

Figure 1.  Ligand-activated p75NTR-mediated signalling pathways. p75NTR is a transmembrane receptor that is cleaved both extracellularly and within the transmemebrane domain. p75NTR, either constitutively or following neurotrophin (NGF) binding, promotes cell death through Chopper domain- and apoptosome-mediated pathways and/or through death domain-activated c-jun kinase (JNK) and nuclear factor kB (NFkB)-mediated pathways. In some environments, neurotrophin binding to p75NTR mediates cell survival or differentiation, or modulates synaptic activity. Aβ peptide binding to p75NTR activates JNK, NFkB and/or Gi/o-proteins, leading to cell death. Aβ peptide binding can also activate PI3K, which promotes survival.

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Aβ binds to p75NTR

  1. Top of page
  2. Abstract
  3. Structure of p75NTR
  4. Aβ binds to p75NTR
  5. Aβ-activated p75NTR-mediated signal cascades
  6. Alternative hypotheses of Aβ-p75NTR-mediated signals
  7. References

In 1997 Yaar et al. reported that Aβ 1–40 binds to and immunoprecipitates with p75NTR (Yaar et al. 1997). This group then went on to demonstrate that the p75NTR-Aβ complex can contain either a sole p75NTR receptor (∼80 kDa) or a receptor complex of ∼230 kDa, proposed to be a trimer of p75NTR (Yaar et al. 2002). The larger molecular weight complex was also observed by Kuner et al. (1998), who used I125-labelled Aβ 1–40 peptide for its visualization. Although other members of the TNFR family signal cell death through trimeric ligand activation and trimeric death domain protein-propagated caspase-8 activation (Liepinsh et al. 1997), there are a number of lines of evidence to suggest that p75NTR does not form trimeric signalling complexes, and that it promotes caspase-9 rather than capsase-8 activation (Coulson et al. 2004). Firstly, the region with homology to the trimeric TNFR death domain does not bind or activate the downstream death domain partners (Liepinsh et al. 1997; Kong et al. 1999). Secondly, although death promotion through p75NTR was first reported as occurring through a monomeric and ligand-free receptor, this was subsequently accepted to be a dimeric ligand-bound signalling complex due to the dimeric nature of neurotrophins (Barrett 2000). However, recent experiments are again challenging this view. Current models include both monomeric and dimeric receptor complexes which might bind with dimeric or tetrameric NGF or proNGF (Lee et al. 2001; He and Garcia 2004; Aurikko et al. 2005). p75NTR also associates with a number of other receptors, sometimes in response to other ligands (Hashimoto et al. 2004a; Nykjaer et al. 2004; Domeniconi et al. 2005), which may make up a tertiary complex. In addition, the metalloprotease-cleaved form of p75NTR might itself propagate signal transduction (Esposito et al. 2001; Jung et al. 2003; Coulson et al. 2004).

So how might Aβ activate p75NTR? Since the NGF and Aβ binding sites within p75NTR appear to be distinct (Susen and Blöchl 2005), it leaves open the possibility that Aβ induces trimerization of p75NTR as first suggested (Yaar et al. 2002). However, Aβ might also regulate preferential interaction of p75NTR with specific co-receptors. Association with sortilin (95 kDa; which also binds pro-neurotrophins Nykjaer et al. 2004) or multimers of the 45 kDa neurotrophin receptor homologue (Kanning et al. 2003; Murray et al. 2004) may account for the observed higher molecular weight product. Alternatively, Aβ could merely be associating with a component of the γ-secretase complex, which in turn associates with p75NTR. If so, without necessarily binding directly, Aβ could modulate γ-secretase cleavage of p75NTR, thereby regulating its signal transduction (Jung et al. 2003; Kanning et al. 2003; Coulson et al. 2004; Domeniconi et al. 2005). Clarification of the components of the Aβ-p75NTR receptor complex may assist in narrowing the array of possible outcomes of p75NTR-mediated signals in neurons.

Similarly, clarification of which form of Aβ preferentially interacts with p75NTR might also elucidate key roles of p75NTR in the aetiology of Alzheimer's disease. Amyloid comes in many forms: soluble prefibrillar (or non-fibril) assemblies, protofibrils (low-n oligomers, fibril intermediates), and fibrillar-plaque amyloid. It is currently thought that soluble but aggregated Aβ is the toxic form, as opposed to monomeric soluble peptides or insoluble aggregates that comprise the amyloid plaques (Morgan et al. 2004; Walsh and Selkoe 2004). The vast majority of toxicity studies ‘age’ Aβ peptides to promote aggregation and toxicity; however, whether the aggregate is fibrillar or disordered affects the peptides' interactions with other proteins, including, presumably, p75NTR (Morgan et al. 2004). Indeed, p75NTR can propagate different signalling cascades depending on whether it is bound by soluble or protofibril peptides (Costantini et al. 2005b). This emphasizes the necessity to characterize the form of peptide in experimental paradigms.

A variety of different-length Aβ peptides also interact with and activate p75NTR signalling, including aggregated Aβ1–40 (Yaar et al. 1997; Kuner et al. 1998; Yaar et al. 2002), soluble oligomeric and aggregated Aβ1–42 (Tsukamoto et al. 2003; Zhang et al. 2003; Hashimoto et al. 2004b; Costantini et al. 2005b; Susen and Blöchl 2005), and oligomeric and aggregated Aβ 23–35 (Kuner et al. 1998; Tsukamoto et al. 2003; Costantini et al. 2005c). Interestingly, the characteristics of p75NTR-mediated cell death and activation of signalling cascades triggered by Aβ do not vary with peptide size (1–40/42 versus 25–35), although the effects are not induced by reverse peptides (e.g. 40–1) or truncated peptides (1–28). This suggests that amino acids within the 29–35 region of the Aβ sequence are crucial for the effects mediated through p75NTR. Thus it is possible that any length of protein containing this sequence might interact with p75NTR or even that Aβ peptides could compete with full-length or fragment forms of APP, which can also mediate p75NTR signalling (Milward et al. 1992; Akar and Wallace 1998). However, since Aβ 25–35 peptide-induced toxicity occurs via a different mechanism from that induced by the physiologically produced peptides (Varadarajan et al. 2001), if p75NTR signals are not exclusively activated by Alzheimer's disease-accumulating Aβ fragments, the Aβ–p75NTR neurotoxicity hypothesis is challenged. Therefore it is crucial that experiments are performed to address this point.

Aβ-activated p75NTR-mediated signal cascades

  1. Top of page
  2. Abstract
  3. Structure of p75NTR
  4. Aβ binds to p75NTR
  5. Aβ-activated p75NTR-mediated signal cascades
  6. Alternative hypotheses of Aβ-p75NTR-mediated signals
  7. References

Aβ binding to p75NTR triggers activation of the downstream signalling molecules c-Jun kinase (JNK), Gi/o-proteins, nuclear factor κB (NFκB) and phosphoinositide-3 kinase (PI3K). Activation of JNK by p75NTR is widely acknowledged as a critical step in its mediation of neural death, being upstream of proapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family members and downstream of the p75NTR-interacting factors NRAGE (neurotrophin receptor-interacting MAGE homologue) and TNF receptor-associated factors (TRAF; Roux and Barker 2002; Coulson et al. 2004; Gentry et al. 2004). In line with these data, aggregated Aβ 1–40 and 1–42 promotes c-jun phosphorylation as an early event in p75NTR-mediated cell death (Yaar et al. 2002; Tsukamoto et al. 2003; Costantini et al. 2005c). Similarly, aggregated Aβ 25–25 promotes p75NTR-mediated cell death, which is also dependent on JNK and p38 activation, as well as the mitogen-activated protein kinases MKK3, 4 and 6 and p53 activity (Costantini et al. 2005c). The activity of these proteins was found to require the death domain region of p75NTR (Perini et al. 2002; Costantini et al. 2005c).

In line with these findings, we have shown that the death domain region of p75NTR activates JNK, but promotes its cascade and cell death more efficiently when coupled with the Chopper domain (W Bruinzeel, EJ Coulson, M Cik, unpublished data). In contrast, the Chopper domain does not alone activate JNK, but initiates the early death-promoting signals mediated through the mitochondria-dependent apoptotic pathway, which appears responsible for most of the death-inducing activity (Coulson et al. 2000b; Coulson et al. 2004). Consistent with these findings, antisense to p75NTR can prevent growth factor withdrawal-induced cell death (Barrett and Bartlett 1994), which is dependent on c-jun activation (Palmada et al. 2002). However, a dominant negative form of the Chopper domain does not block growth factor withdrawal-induced cell death but inhibits p75NTR-mediated, c-jun-independent cell death in vitro and in vivo (Coulson et al. 2000b; Palmada et al. 2002). One interpretation of these data is that p75NTR can mediate two distinct death cascades; signal transduction and the rate of death induced by Aβ more closely resembles the outcomes seen with growth factor withdrawal. The circumstances in which these two different death cascades are activated, if indeed the pathways are distinct, remain to be clarified.

It has also been shown that Aβ-induced p75NTR-mediated cell death signals utilize Gi/o proteins, with pharmacological and genetic prevention of Gi/o-protein activation inhibiting Aβ-induced cell death. The 5th helix of the death domain has been shown to mediate this activity (Tsukamoto et al. 2003; Hashimoto et al. 2004b). Interestingly, G-protein activation has not been demonstrated for neurotrophin activation of p75NTR, although recently we reported that p75NTR activates a Gi/o-protein-activated potassium channel to mediate cell death (Coulson et al. 2004). Remarkably, Aβ toxicity via Gi/o-proteins is enhanced by p75NTR's association with its homologue NGF receptor homologue 2 (NRH2), which lacks most of the ligand-binding domain (Hashimoto et al. 2004b) but has homology to the TNFR death domain and is highly conserved within the transmembrane and Chopper domains (Kanning et al. 2003; Murray et al. 2004). Therefore activation of specific p75NTR-mediated pathways may depend on the association of p75NTR with specific co-receptors (Nykjaer et al. 2004; Domeniconi et al. 2005).

Aβ also stimulates p75NTR-mediated NFκB activation. While most consistently noted for its ability to promote cell death in the context of neurotrophins (Carter et al. 1996; Yeiser et al. 2004; Allen et al. 2005), dimerization of p75NTR mediates NFκB-dependent survival through association with receptor interacting protein-2 (RIP2) and TRAF proteins (Ye et al. 1999; Khursigara et al. 2001). However, it seems that in the context of Aβ toxicity, NFκB activation by the death domain region of p75NTR promotes cell death (Kuner et al. 1998; Costantini et al. 2005c). Unlike neurotrophin-mediated NFκB activation, Aβ-mediated NFκB activity is a consequence of JNK activity (Costantini et al. 2005c), indicating the involvement of a different signalling pathway. In a broader context, NFκB activity has been reported both to mediate Aβ-induced cell death and to be protective. This signalling dichotomy also occurs with other NFκB activators, including TNF. NFκB signalling outcomes depend on the subunits activated; for example, c-rel/p65 and c-rel/p50 regulate a cell's response to mitogens, whereas p65 but not p50 has an antiapoptotic effect (Hayden and Ghosh 2004). It is not clear from the experiments performed to date which NFκB subunits are activated by p75NTR and whether this varies with cell type, context or ligand.

Recently, it was shown in neuroblastoma cells that activation of PI3K via the Chopper domain is important for blocking the toxicity of Aβ protofibrils (Costantini et al. 2005b), whereas p75NTR expression is required for Aβ fibril toxicity (Perini et al. 2002). Interestingly, in primary neuronal cultures, p75NTR blocked the toxicity of both fibrillar and non-fibrillar Aβ through PI3K-dependent, Akt-independent signals (Zhang et al. 2003). p75NTR has been reported to promote survival in a number of other situations, including following growth factor withdrawal, through activation of the PI3K pathway. However, this is dependent on Shc2 and Akt phosphorylation (Roux et al. 2001; Epa et al. 2004), making it difficult to place the results of Costantini et al. (2005b,c) and Zhang et al. (2003) in a broader context.

A simplistic summary of the data suggests that Aβ promotes p75NTR-mediated survival in neurons and death in proliferating cell lines. However, this is in opposition to the outcomes of neurotrophin-mediated p75NTR signalling. The array of different activation signals and opposing outcomes highlights a major limitation inherent in the large majority of reports characterizing the role of p75NTR in the neurotoxicity of Aβ, i.e, they are in vitro studies using p75NTR transfection of immortalized cell lines which may or may not contain endogenous co-receptors and assay downstream signals without clearly defined outcomes. There is also an underlying assumption that when Aβ is toxic to p75NTR-expressing cells it is due to promotion of death rather than disruption of survival. Therefore it is important to consider alternative hypotheses to explain the observed outcomes of Aβ-induced p75NTR-mediated signalling.

Alternative hypotheses of Aβ-p75NTR-mediated signals

  1. Top of page
  2. Abstract
  3. Structure of p75NTR
  4. Aβ binds to p75NTR
  5. Aβ-activated p75NTR-mediated signal cascades
  6. Alternative hypotheses of Aβ-p75NTR-mediated signals
  7. References

Given the absence of a definitive in vivo study of p75NTR signals mediated by amyloid, speculation on the topic is relatively unrestricted. Indeed, it seems remarkable that an analysis of amyloid-producing p75NTR-deficient mice has not been reported. Nor has Aβ peptide been injected into brains of p75NTR–/– mice to look at its effects on the cholinergic, or any other, system (Giovannini et al. 2002; Boyd-Kimball et al. 2005). Perhaps this is because such analyses are far from straightforward. There has been decade-long uncertainty as to the relative number of cholinergic forebrain neurons in p75NTR–/– mice compared to their wild-type counterparts, with a further complication lying in the possible existence of background strain- and splicing-dependent, death-promoting transcripts in these mice (Naumann et al. 2002 and refs therein; Murray et al. 2003; Paul et al. 2004). However, the persistent reports that Aβ and p75NTR modulate each other's actions suggest that such analyses would be a scientifically rewarding albeit challenging endeavour.

So what would be the expected outcomes? One model based on the current data is that preformed p75NTR dimers (Aurikko et al. 2005) are either silent or constitutively signalling survival, and that Aβ amyloid binding disrupts their tertiary or macromolecular structure, thereby triggering death. Depending on the cellular context and disruption, death could occur via an active mechanism or be similar to growth factor withdrawal. This model is consistent with the ability of growth factors, including NGF, to override Aβ-induced death (Kuner et al. 1998; Ye et al. 1999; Hashimoto et al. 2004b; Costantini et al. 2005c) by promoting association with and signalling through tyrosine kinase receptors, restoring equilibrium to disrupted intramembrane proteolysis or restoring macromolecular and structural normality and hence the status quo. However, this model does not account for the results in primary neurons (Zhang et al. 2003). To determine the signalling and functional outcomes in adult neurons, in vivo experiments must be performed.

It is also possible that Aβ-induced p75NTR signalling regulates other cellular processes. p75NTR has been shown to slow proliferation and promote differentiation of neural and non-neural cells in vitro (Cattaneo and McKay 1990; Seidl et al. 1998; Chittka and Chao 1999). In cultured cell lines, as opposed to post-mitotic neurons, the major components of these signal cascades are present. Aβ-stimulated reduction of cell cycle time or terminal differentiation could therefore reduce cell numbers through lack of proliferation, or result in reduced viability due to the absence of an appropriate cellular context. Thus, reduced cell number would only be observed in proliferating cells (primary or immortalized) and not in differentiated neurons. In support of this model, Aβ can trigger differentiation of progenitor cells derived from adult neurogenic regions. Indeed, the observed promotion of oligomeric Aβ-induced neurogenesis in Alzheimer's disease (Jin et al. 2004a,b; López-Toledano and Shelanski 2004; Chevallier et al. 2005) could theoretically be mediated via p75NTR.

Other possible avenues for exploration in vivo and in vitro involve the p75NTR-mediated regulation of synaptic activity in the hippocampus (Rosch et al. 2005; Woo et al. 2005) and axonal outgrowth (Kohn et al. 1999; Singh and Miller 2005). These are emerging fields of p75NTR research which emulate death/survival signalling: the processes are enhanced by mature neurotrophin-Trk-mediated signals and are inhibited through pro-neurotrophins and p75NTR. p75NTR-mediated regulation of these cellular processes following Aβ treatment has not been extensively examined (Susen and Blöchl 2005). However, downstream signals that modulate these processes would have profoundly different functional outcomes when assayed in non-neuronal cells, which covers the majority of studies to date. Remarkably, Aβ-p75NTR-mediated modulation of these processes could underlie the symptoms of dementia (Walsh and Selkoe 2004). Indeed mis-regulation of synaptic or cellular plasticity may cause the loss of neurons observed in later stages of disease.

In summary, despite a dozen reports showing promotion of death signalling through p75NTR by Aβ, and the beginnings of a signalling consensus, it is by no means clear whether Aβ toxicity is mediated by p75NTR in vivo. The field still needs to address whether physiological Aβ peptide, as well as neurotrophins, activate robust and distinct p75NTR signalling cascades, and what regulates the two-way relationship between Aβ generation, presenilin activity and p75NTR processing. Although the promising p75NTR-Aβ faction has many avenues to explore and much rigorous experimentation ahead, this work seems guaranteed to generate interesting outcomes. Aβ-regulated signalling through p75NTR may yet explain a number of the neurodegenerative characteristics of Alzheimer's disease.

References

  1. Top of page
  2. Abstract
  3. Structure of p75NTR
  4. Aβ binds to p75NTR
  5. Aβ-activated p75NTR-mediated signal cascades
  6. Alternative hypotheses of Aβ-p75NTR-mediated signals
  7. References
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