Dysregulation of neurotrophin signalling has been implicated in a number of neurodegenerative conditions, including Alzheimer's disease, and can result in reduced survival signalling and a propensity for apoptosis. For instance, amyloid beta (Aβ) neurotoxicity can be directly mediated by the pan p75 neurotrophin receptor (p75NTR), triggering signalling pathways that result in neuronal degeneration (Coulson et al. 2009). In the current issue, Saadipour and colleagues report that Aβ, acting through p75NTR, can increase the expression of another pro-apoptotic neurotrophin receptor, sortilin (Saadipour et al. 2013). Although the physiological relevance of sortilin up-regulation is currently unclear, some implications of this finding are discussed below.
The neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3), are key modulators of normal neuronal function in the adult brain. Their actions are mediated by ligand-specific Trk receptors and p75NTR, with a third receptor, sortilin, binding the immature or pro-neurotrophins (Skeldal et al. 2011). Trk receptor function is predominantly neurotrophic and can be facilitated by the formation of a p75NTR/Trk receptor complex. Neurotrophic signalling typically results in cell and neurite growth, enhanced synaptic activity and neuronal survival. However, p75NTR is also strongly implicated in mediating both atrophic (e.g. neurite retraction, long-term depression) and apoptotic signalling when Trk receptors are not co-incidentally stimulated. Such signalling can be initiated in response to pro-neurotrophins in concert with sortilin, or in response to other ligands, including Aβ. Although it is accepted that sortilin plays an important role in p75NTR-mediated apoptotic signalling in conditions such as acute injury (Nykjaer and Willnow 2012), and that it acts to decrease Aβ burden in transgenic models of Alzheimer's disease (Carlo et al. 2013), its role in cell death in the latter condition remains unclear.
The major finding of Saadipour and colleagues is that Aβ treatment of neurons in vitro results in increased sortilin expression. The authors also found an increase in sortilin expression in the brains of Aβ over-expressing transgenic mice, and in the post-mortem tissue of a small number (n = 4 subjects per group) of Alzheimer's disease patients. In contrast, a much larger study (> 50 subjects per group) found no significant change (Mufson et al. 2010), although the authors reported a significant correlation between the severity of disease and extent of sortilin expression. Given that sortilin is associated with apoptotic signalling triggered by pro-neurotrophins, which are also up-regulated in Alzheimer's disease brains, it is perhaps not surprising that a clear difference between the expression levels of sortilin in the pathological and healthy control tissue was not found. One explanation is that neurons expressing high levels of sortilin in the context of high concentrations of pro-neurotrophins may be more likely to die, thereby reducing overall sortilin levels in the tissue while also contributing to disease progression.
The triggers for sortilin up-regulation through p75NTR in the Saadipour study were Aβ and proBDNF, both of which are capable of inducing neuronal apoptosis, whereas mature BDNF, which is more likely to engage endogenously expressed TrkB, did not have the same effect. However, inhibiting activation of c-jun kinase (JNK), through which p75NTR typically signals apoptosis (Skeldal et al. 2011), had no effect on Aβ-induced sortilin expression. Rather, Rho activity was required for Aβ to cause up-regulation of sortilin expression. It has been widely reported that activation of Rho by p75NTR, including in response to proBDNF, is required for p75NTR-mediated neurite retraction (Sun et al. 2012). This suggests that Aβ-induced sortilin up-regulation is not a typical pro-apoptotic response. Indeed, neither Aβ nor proBDNF treatment resulted in neurotoxicity in the Saadipour study. Therefore, both atrophic and apoptotic signalling mediated by p75NTR can be initiated by the same ligands, but their concentrations and/or other factors determine which signalling pathway is propagated.
Although apoptotic or atrophic signalling is associated with disease conditions, a number of related processes are also important for normal brain function. Long-term depression, dendritic spine and neurite retraction and, in nervous system development, apoptosis, are important components of optimal nervous system function. It is only when atrophic signalling is no longer balanced by trophic signalling that neurodegeneration occurs. Similarly, Aβ is not always neurotoxic, but is produced by healthy neural cells and has trophic attributes at normal endogenous concentrations; it is only when genetic pre-dispositions or cellular processes lead to the accumulation of Aβ that it becomes neurotoxic. Therefore, signalling via p75NTR to up-regulate the expression of sortilin, albeit that this is a co-receptor strongly associated with apoptotic signalling, does not necessarily increase the risk of neurodegeneration.
Sortilin is a member of a family of VSp10-like receptor proteins that also includes SorLa and SorCS1, 2 and 3. All family members control the trafficking and/or cleavage of amyloid precursor protein (APP), with SorLa normally maintaining Aβ generation below neurotoxic levels (Nykjaer and Willnow 2012). Sortilin can act in ways that might reduce the risk of Aβ toxicity; it binds to and promotes α-cleavage of APP, precluding Aβ production, and is also responsible for apolipoprotein E-mediated cellular uptake and degradation of extracellular Aβ (Carlo et al. 2013; Gustafsen et al. 2013). In the context of acutely increased Aβ production, a further increase in sortilin expression via p75NTR may subsequently down-regulate Aβ production and reduce extracellular Aβ concentrations. This would provide a novel feedback loop that ensures some degree of Aβ homeostasis. At the same time, if pro-neurotrophins are expressed only at levels and in locations where they are mediate essential processes such as neurite pruning, activation of p75NTR and sortilin would be unlikely to trigger apoptosis in the context of sufficient Trk receptor activity (Fig. 1a).
However, in the context of prodromal disease, where neurotrophins and/or Aβ levels are already or are becoming chronically dysregulated, sortilin-mediated signalling may be one of the factors that triggers a fateful feed-forward loop that turns regular atrophic signalling into apoptotic signalling, thereby contributing to the disease phenotype (Fig. 1b). Down-regulation of Trk receptor expression, with maintained p75NTR expression, coincides with the progression from healthy ageing to cognitive impairment (Ginsberg et al. 2006). In such a context, p75NTR would not be bound to Trk receptors, and therefore able to form the well-characterized apoptotic co-receptor complex with sortilin. Formation of this complex would be further facilitated not only by the enhanced expression of sortilin but also by the binding of pro-neurotrophins, the expression of which is similarly increased at this time (Mufson et al. 2012). As this co-receptor complex favours activation of the JNK rather than the Rho pathway, apoptotic rather than atrophic signals would likely result (Fig. 1b). Indeed, increased levels of activated JNK are found within Alzheimer's disease tissue in which proNGF expression is increased and TrkA expression is reduced (Mufson et al. 2012), supporting this idea.
The regulation of neurotrophic pathways and the metabolism of APP and Aβ are increasingly reported to be bidirectional. The findings of Saadipour et al. reinforce the fact that this cross-talk exists but highlight the fact that it is complex and multi-dimensional. These authors have revealed a novel regulation loop, and although the functional significance of this Aβ-induced p75NTR-mediated sortilin expression remains to be determined, we speculate that the resulting outcomes will likely depend on the neuronal context in which it occurs.