Is there a role for the p75 neurotrophin receptor in mediating degeneration during oxidative stress and after hypoxia?

Cholinergic basal forebrain (cBF) neurons are particularly vulnerable to degeneration following trauma and in neurodegenerative conditions. One reason for this is their characteristic expression of the p75 neurotrophin receptor (p75(NTR)), which is up-regulated and mediates neuronal death in a range of neurological and neurodegenerative conditions, including dementia, stroke and ischaemia. The signalling pathway by which p75(NTR) signals cell death is incompletely characterised, but typically involves activation by neurotrophic ligands and signalling through c-Jun kinase, resulting in caspase activation via mitochondrial apoptotic signalling pathways. Less well appreciated is the link between conditions of oxidative stress and p75(NTR) death signalling. Here, we review the literature describing what is currently known regarding p75(NTR) death signalling in environments of oxidative stress and hypoxia to highlight the overlap in signalling pathways and the implications for p75(NTR) signalling in cBF neurons. We propose that there is a causal relationship and define key questions to test this assertion.