Abstract
Profound and early basal forebrain cholinergic neuron (BFCN) degeneration is a hallmark of Alzheimer’s disease (AD). Loss of synapses between basal forebrain and hippocampal and cortical target tissue correlates highly with the degree of dementia and is thought to be a major contributor to memory loss. BFCNs depend for their survival, connectivity and function on the neurotrophin nerve growth factor (NGF) which is retrogradely transported from its sites of synthesis in the cortex and hippocampus. The form of NGF found in human brain is proNGF. ProNGF binds to the NGF receptors TrkA and p75NTR, but it binds more strongly to p75NTR and more weakly to TrkA than does mature NGF. This renders proNGF more sensitive to receptor balance than mature NGF. In the healthy brain, where BFCNs express both TrkA and p75NTR, proNGF is neurotrophic, activating TrkA-dependent signaling pathways such as MAPK and Akt-mTOR and eliciting cell survival and neurite outgrowth. However, if TrkA is lost or if p75NTR is increased, proNGF activates p75NTR-dependent apoptotic pathways such as JNK. This receptor sensitivity serves as a neurotrophic/apoptotic switch that eliminates BFCNs that cannot maintain TrkA/p75NTR balance and therefore synaptic connections with their targets. TrkA is increasingly lost in mild cognitive impairment (MCI) and AD. In addition, proNGF accumulates at BFCN terminals in cortex and hippocampus, reducing the amount of trophic factor that reaches BFCN cell bodies. The loss of TrkA and accumulation of proNGF occur early in MCI and correlate with cognitive impairment. Increased levels of proNGF and reduced levels of TrkA lead to BFCN neurodegeneration and eventual p75NTR-dependent apoptosis. In addition, in AD BFCNs suffer from reduced TrkA-dependent retrograde transport which reduces neurotrophic support. Thus, BFCNs are particularly vulnerable to AD due to their dependence upon retrograde trophic support from proNGF signaling and transport.
Highlights
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication
ProNGF activates TrkA even when incubated for 1 h in the presence of a furin inhibitor which allows uptake but not cleavage (Masoudi et al, 2009). These results demonstrated that cleavage to mature nerve growth factor (NGF) is not required for proNGF signaling and implicate proNGF as the form of NGF that normally signals and is endocytosed
ProNGF is abundant in the CNS and can have both neurotrophic and apoptotic activities, depending on the receptor complement
Summary
All neuronal cells require neurotrophic factors for their proper function and survival. The proNGF found in these tissues is not an intracellular precursor; it has since been accepted that secretion of unprocessed proNGF occurs from many cells and tissues, including neurons and astrocytes (Chen et al, 1997; Delsite and Djakiew, 1999; Mowla et al, 1999; Yardley et al, 2000; Lee et al, 2001; Fahnestock et al, 2004a; Bruno and Cuello, 2006), and that proNGF is the major species in both PNS (Figure 1B) and CNS tissues (Figure 1A; Fahnestock et al, 2001; Bierl et al, 2005) This distinction between the pro and mature isoforms of NGF is extremely important, as they have the potential to activate different signaling pathways, a behavior completely contingent on the receptors they bind to. Once the biological significance of proNGF was made clear, it was found that many of the same Trk- and p75NTR-induced pathways are activated by proNGF
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