ProNGF and Neurodegeneration in Alzheimer's Disease
- PMID: 30853882
- PMCID: PMC6395390
- DOI: 10.3389/fnins.2019.00129
ProNGF and Neurodegeneration in Alzheimer's Disease
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.
Figures


Similar articles
-
Effects of Reactive Oxygen and Nitrogen Species on TrkA Expression and Signalling: Implications for proNGF in Aging and Alzheimer's Disease.Cells. 2021 Aug 4;10(8):1983. doi: 10.3390/cells10081983. Cells. 2021. PMID: 34440751 Free PMC article. Review.
-
Age-induced nitrative stress decreases retrograde transport of proNGF via TrkA and increases proNGF retrograde transport and neurodegeneration via p75NTR.Front Mol Neurosci. 2023 Nov 13;16:1241420. doi: 10.3389/fnmol.2023.1241420. eCollection 2023. Front Mol Neurosci. 2023. PMID: 38025269 Free PMC article.
-
Compromise of cortical proNGF maturation causes selective retrograde atrophy in cholinergic nucleus basalis neurons.Neurobiol Aging. 2018 Jul;67:10-20. doi: 10.1016/j.neurobiolaging.2018.03.002. Epub 2018 Mar 9. Neurobiol Aging. 2018. PMID: 29609077
-
Dissecting the involvement of tropomyosin-related kinase A and p75 neurotrophin receptor signaling in NGF deficit-induced neurodegeneration.Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12299-304. doi: 10.1073/pnas.1007181107. Epub 2010 Jun 21. Proc Natl Acad Sci U S A. 2010. PMID: 20566851 Free PMC article.
-
Cholinotrophic molecular substrates of mild cognitive impairment in the elderly.Curr Alzheimer Res. 2007 Sep;4(4):340-50. doi: 10.2174/156720507781788855. Curr Alzheimer Res. 2007. PMID: 17908035 Review.
Cited by
-
Effects of Reactive Oxygen and Nitrogen Species on TrkA Expression and Signalling: Implications for proNGF in Aging and Alzheimer's Disease.Cells. 2021 Aug 4;10(8):1983. doi: 10.3390/cells10081983. Cells. 2021. PMID: 34440751 Free PMC article. Review.
-
Non-Invasive Assessment of Neurogenesis Dysfunction in Fetuses with Early-Onset Growth Restriction Using Fetal Neuronal Exosomes Isolating from Maternal Blood: A Pilot Study.Int J Mol Sci. 2025 Feb 11;26(4):1497. doi: 10.3390/ijms26041497. Int J Mol Sci. 2025. PMID: 40003962 Free PMC article.
-
Reduction of acetylcholine in the hippocampus of hippocampal cholinergic neurostimulating peptide precursor protein knockout mice.Sci Rep. 2021 Nov 11;11(1):22072. doi: 10.1038/s41598-021-01667-8. Sci Rep. 2021. PMID: 34764402 Free PMC article.
-
Inhibition of TLR4 Induces M2 Microglial Polarization and Provides Neuroprotection via the NLRP3 Inflammasome in Alzheimer's Disease.Front Neurosci. 2020 May 20;14:444. doi: 10.3389/fnins.2020.00444. eCollection 2020. Front Neurosci. 2020. PMID: 32508567 Free PMC article.
-
Profiling the autoantibody repertoire reveals autoantibodies associated with mild cognitive impairment and dementia.Front Neurol. 2023 Nov 30;14:1256745. doi: 10.3389/fneur.2023.1256745. eCollection 2023. Front Neurol. 2023. PMID: 38107644 Free PMC article.
References
-
- Auld D. S., Mennicken F., Day J. C., Quirion R. (2001a). Neurotrophins differentially enhance acetylcholine release, acetylcholine content and choline acetyltransferase activity in basal forebrain neurons. J. Neurochem. 77 253–262. - PubMed
Publication types
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials
Miscellaneous