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Review
. 2019 Feb 22:13:129.
doi: 10.3389/fnins.2019.00129. eCollection 2019.

ProNGF and Neurodegeneration in Alzheimer's Disease

Affiliations
Review

ProNGF and Neurodegeneration in Alzheimer's Disease

Margaret Fahnestock et al. Front Neurosci. .

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.

Keywords: TrkA; apoptosis; basal forebrain cholinergic neurons; nerve growth factor; neurotrophins; p75NTR; retrograde transport; survival.

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Figures

FIGURE 1
FIGURE 1
Western blot probing for NGF immunoreactivity in human brain tissue (A) and peripheral targets (B) demonstrating the presence of proNGF and the absence of mature NGF in the indicated areas (ec, external carotid; sm, submandibular gland; pin, pineal gland; bv, extracerebral blood vessels). (A) Reprinted from Fahnestock et al. (2001), with permission from Elsevier. (B) Reprinted from Bierl et al. (2005), with permission from Elsevier.
FIGURE 2
FIGURE 2
Diagram of the various pathways activated by TrkA and p75NTR. TrkA in isolation activates pro-survival pathways including the Ras-MAP kinase, PLCγ, and PI3 kinase/Akt pathways. p75NTR, when complexed with TrkA, increases pro-survival signaling through TrkA. p75NTR in isolation can also signal survival via the NF-κB and PI3/Akt pathways. p75NTR in isolation activates apoptosis via sphingomyelinase/ceramide, JNK, c-Jun phosphorylation and caspases 3, 6, and 9. When complexed with sortilin, p75NTR binds proNGF with a higher affinity than NGF, signaling cell death through the same pathways. p75NTR can also cause growth cone retraction/neurite outgrowth inhibition when complexed with the Nogo-66 receptor and its ligand Lingo-1. The balance of Trks and p75NTR is crucial to the functional outcome of neurotrophin binding.

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