. Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury. Nat Neurosci. 2007 Nov;10(11):1449-57. PubMed.


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  1. The pan neurotrophin receptor p75NTR is known to increase the binding affinity of neurotrophins to the Trk family of tyrosine kinase receptors, which mediate a variety of trophic activities (Chao, 2003). However, in contrast to its ability to modulate trophic activities, p75 also binds pro-neurotrophins to induce apoptosis in several neuronal and non-neuronal cell populations during development, aging, and injury (Rabizadeh et al., 1993; Cotrina et al., 2000; Friedman 2000; Casaccia-Bonnefil et al, 1996; Beattie et al., 2002; Harrington et al., 2004). The expression and activity of p75NTR in the nervous system is highest during development when critical pruning of unnecessary cells occurs (Bamji et al., 1998; Frade and Barde, 1999). However, one of the few neuronal populations that express p75NTR throughout life are the basal forebrain cholinergic neurons (BFCNs), whose degeneration during Alzheimer disease is believed to cause some of the debilitating cognitive effects observed in AD patients. Interestingly pro-NGF, a pro-apoptotic p75 ligand, is also significantly increased the brains of AD patients (Fahnestock et al., 2001; Peng et al., 2004). The exact contribution of pro-NGF/p75 signaling in cell loss during AD has been difficult to assess because p75 binds multiple ligands and acts as a co-receptor to participate in a variety of cellular functions.

    Recently, it was demonstrated that p75NTR mediates its pro-neurotrophin-dependent pro-apoptotic effects by forming a complex with the Vps10p domain receptor sortilin (Nykjaer et al., 2004). This complex was demonstrated to induce apoptosis in SCG neurons in vitro, even in the presence of the pro-survival Trk neurotrophin receptors. Although sortilin was shown to be a critical component for transducing the pro-neurotrophin/p75NTR apoptotic signal in vitro, its contribution to in vivo apoptotic processes was unknown. In this paper, Jansen et al. address the in vivo role of sortilin by generating a sortilin-deficient mouse (Sort1-/-). To begin, they showed that cultured Sort1-/- SCGs neurons were resistant to pro-neurotrophin induced apoptosis, similar to the p75NTR-deficient neurons, confirming the previous in vitro observation that sortilin activity was necessary for pro-neurotrophin/p75NTR induced apoptosis. However, surprisingly Sort1-/- mice did not have significantly different numbers of SCG neurons during development in vivo, unlike the p75NTR-deficient mouse (Ngfr-/-), which showed a lack of developmental loss of SCG neurons. This novel observation indicates that while the developmental loss of SCG neurons appears to be p75NTR-dependent, it is not sortilin-dependent and is therefore not regulated by pro-neurotrophins. Sortilin does appear to be involved in age-related loss of neurons in adult SCGs, as the authors demonstrate that Sort1-/- mice, similar to Ngfr-/- mice, have increased SCG neurons in 60-week-old mice compared to wild-type littermates. Also, pro-neurotrophins were increased in aged SCGs, which appeared to be due to increased local expression in the SCGs, rather than retrograde transport. This age-dependent apoptosis of SCGs is actively mediated by pro-neurotrophins in a p75NTR/sortilin-dependent manner, and is not simply due to an age-dependent loss of trophic support. Sortilin was also shown to be necessary for regulating developmental cell-death in the mouse retina, as well as inducing cell death after motor neuron injury. Interestingly, sympathetic neuron projections appeared to be dependent on p75NTR expression for their survival, as there was significant atrophy with age observed only in the Ngfr-/- mice, demonstrating the trophic activity of p75NTR.

    This paper provides some extremely important insights into the nature of sortilin/p75NTR biology that could potentially be applied to studying AD. First, it is apparent that the sortilin/p75NTR receptor complex is necessary to mediate pro-neurotrophin induced apoptosis. It is known that sortilin and p75NTR are present in the adult cortex, hippocampus, and basal forebrain and that pro-NGF is increased in these areas in AD patients. Therefore it is reasonable to hypothesize that increased pro-NGF could lead to increased apoptosis in a sortilin/p75NTR-dependent manner during AD. The authors found that pro-neurotrophins were necessary for the induction of age-related cell death of SCGs and injury-related death of motor neurons, proving that cell death with age and pathophysiology in these cells is actively regulated by pro-neurotrophins, not simply due to a lack of trophic support as previously hypothesized. Furthermore, Volosin et al., 2006, previously demonstrated that in cultured basal forebrain neurons sortilin was necessary for pro-NGF induced apoptosis and that death can be induced in these cells even in the presence of activated Trk receptors. It is unknown if pro-neurotrophins can induce BFCN death in vivo in the presence of Trk signaling, but it appears to be a likely possibility that pro-neurotrophins could actively induce death in these cells irrespective of Trk signaling. This would indicate that perhaps the sortilin/p75NTR receptor complex is a more efficacious therapeutic target for AD than the therapies currently being investigated that aim to increase the mature NGF/TrkA signaling. Establishing the role of pro-neurotrophin/sortilin/p75 signaling in regulating cell death of BFCNs in relation to mature-neurotrophin/Trk signaling would be an important contribution to understanding basal forebrain biology and its relevance to AD pathogenesis and treatment.


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