Induction of cell death by endogenous nerve growth factor through its p75 receptor

Frade, José Marı́a; Rodríguez‐Tébar, Alfredo; Barde, Yves‐Alain

doi:10.1038/383166a0

Cited by 669 publications

(73 citation statements)

References 25 publications

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“…For example, in the presence of NGF, p75 NTR can rescue peripheral cell cultures from apoptosis (Gentry et al, 2000; Roux et al, 2001). However, in central neurons and oligodendrocytes, NGF stimulation of p75 NTR in the absence of TrkA more commonly triggers apoptosis (Casaccia-Bonnefil et al, 1996; Frade et al, 1996; Friedman, 2000; Yoon et al, 1998). A putative proapoptotic role for p75 NTR has been demonstrated following the withdrawal of neurotrophic support (Martin et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

Pretangle pathology within cholinergic nucleus basalis neurons coincides with neurotrophic and neurotransmitter receptor gene dysregulation during the progression of Alzheimer's disease

Tiernan

Ginsberg

et al. 2018

Neurobiology of Disease

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Cholinergic basal forebrain neurons of the nucleus basalis of Meynert (nbM) regulate attentional and memory function and are exquisitely prone to tau pathology and neurofibrillary tangle (NFT) formation during the progression of Alzheimer’s disease (AD). nbM neurons require the neurotrophin nerve growth factor (NGF), its cognate receptor TrkA, and the pan-neurotrophin receptor p75NTR for their maintenance and survival. Additionally, nbM neuronal activity and cholinergic tone are regulated by the expression of nicotinic (nAChR) and muscarinic (mAChR) acetylcholine receptors as well as receptors modulating glutamatergic and catecholaminergic afferent signaling. To date, the molecular and cellular relationships between the evolution of tau pathology and nbM neuronal survival remain unknown. To address this knowledge gap, we profiled cholinotrophic pathway genes within nbM neurons immunostained for pS422, a pretangle phosphorylation event preceding tau C-terminal truncation at D421, or dual-labeled for pS422 and TauC3, a later stage tau neo-epitope revealed by this same C-terminal truncation event, via single-population custom microarray analysis. nbM neurons were obtained from postmortem tissues from subjects who died with an antemortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild/moderate AD. Quantitative analysis revealed significant downregulation of mRNAs encoding TrkA as well as TrkB, TrkC, and the Trk-mediated downstream pro-survival kinase Akt in pS422+ compared to unlabeled, pS422-negative nbM neurons. In addition, pS422+ neurons displayed a downregulation of transcripts encoding NMDA receptor subunit 2B, metabotropic glutamate receptor 2, D2 dopamine receptor, and β1 adrenoceptor. By contrast, transcripts encoding p75NTR were downregulated in dual-labeled pS422+/TauC3+ neurons. Appearance of the TauC3 epitope was also associated with an upregulation of the α7 nAChR subunit and differential downregulation of the β2 nAChR subunit. Notably, we found that gene expression patterns for each cell phenotype did not differ with clinical diagnosis. However, linear regression revealed that global cognition and Braak stage were predictors of select transcript changes within both unlabeled and pS422+/TauC3™ neurons. Taken together, these cell phenotype-specific gene expression profiling data suggest that dysregulation of neurotrophic and neurotransmitter signaling is an early pathogenic mechanism associated with NFT formation in vulnerable nbM neurons and cognitive decline in AD, which may be amenable to therapeutic intervention early in the disease process.

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Section: Discussionmentioning

confidence: 99%

Pretangle pathology within cholinergic nucleus basalis neurons coincides with neurotrophic and neurotransmitter receptor gene dysregulation during the progression of Alzheimer's disease

Tiernan

Ginsberg

et al. 2018

Neurobiology of Disease

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“…It binds to the specific high-affinity tyrosine kinase receptor TrkA. The functions of the neurotrophic factors are diverse, including neurogenesis, growth, differentiation, survival, neurite outgrowth and axon regeneration [7,8,9]. …”

Section: Discussionmentioning

confidence: 99%

Nerve Growth Factor Helps Protect Retina in Experimental Retinal Detachment

Sun

Xu²,

Wang³

et al. 2007

Ophthalmologica

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Purpose: To investigate the expression of nerve growth factor (NGF) and its receptor TrkA on the retina at different time points after retinal detachment (RD) and the protection effect of NGF in experimental RD. Methods: Sprague-Dawley rats were used as an RD animal model by injection of 0.1% sodium hyaluronate under the neurosensory retina. The expression of endogenous NGF and its receptor TrkA in the rat retina was detected using immunohistochemistry. The NGF (5 µg/eye) or phosphate-buffered saline were injected separately into vitreous every 4 days after the RD. The rat eyes were then observed at various time points. Morphologic changes were investigated by light microscopy. Retinal gliosis was detected by glial fibrillary acidic protein labeling. Results: The expression of endogenous NGF and TrkA was upregulated during RD procedure. Most of the NGF-treated retina had a well-organized structure. In NGF-treated RD eyes, the cells were still significantly more numerous than in phosphate-buffered-saline-treated retina. Glial fibrillary acidic protein labeling increased quickly after RD; the NGF-treated retina had less reactive gliosis than the control groups. Conclusions: Intravitreal injection of exogenous NGF can protect retinal cells from degeneration in experimental RD. It may exert its protective action by preventing the apoptosis of retinal cells after RD.

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“…The p75 receptor can promote neuronal apoptosis in the absence of Trk receptors [33,34,48]; for example, nerve growth factor causes the death of retinal neurons that express p75 but not TrkA [48]. Also, BDNF activates p75 to induce apoptosis of sympathetic neurons [33], which do not express TrkB.…”

Section: Discussionmentioning

confidence: 99%

“…This finding suggests that p75 plays a different role in the development of the taste system compared with other systems [33,48,49], perhaps due to differences among systems in Trk receptor function. In the retina [48], sympathetic ganglia [33], and dorsal root ganglia [49], p75 induces apoptosis specifically in the absence of TrkA. Thus, TrkB may regulate cell death differently than TrkA [49], and the actions of p75 may differ in the absence of these two receptor types.…”

Section: Discussionmentioning

confidence: 99%

The neurotrophin receptor p75 regulates gustatory axon branching and promotes innervation of the tongue during development

Huang

Krimm

2014

Neural Dev

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BackgroundBrain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4) regulate the survival of gustatory neurons, axon growth and branching, and innervation of taste buds during development. These actions are largely, but not completely, mediated through the tyrosine kinase receptor, TrkB. Here, we investigated the role of p75, the other major receptor for BDNF and NT4, in the development of the taste system.ResultsWe found that p75−/−mice showed delayed axon outgrowth and reduced branching of gustatory axons at embryonic day (E)13.5. From E14.5 to E18.5, gustatory neurons innervated fewer papillae and completely failed to innervate the mid-region of the tongue in p75−/−mice. These early effects of the p75 mutation on gustatory axons preceded the loss of geniculate ganglion neurons starting at E14.5 and also contributed to a loss of taste buds at and after birth. Because knockouts for the TrkB receptor (TrkB−/−) do not lose as many taste buds as hybrid knockouts for its two ligands (BDNF and NT4), we asked if p75 maintains those additional taste buds in the absence of TrkB. It does not; hybrid TrkB−/−/p75−/−mice had more taste buds than TrkB−/−mice; these additional taste buds were not due to an increase in neurons or innervation.Conclusionsp75 regulates gustatory neuron axon branching and tongue innervation patterns during taste system development. This function is likely accomplished independently of BDNF, NT4, and TrkB. In addition, p75 does not support the remaining neurons or taste buds in TrkB−/−mice.

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Induction of cell death by endogenous nerve growth factor through its p75 receptor

Cited by 669 publications

References 25 publications

Pretangle pathology within cholinergic nucleus basalis neurons coincides with neurotrophic and neurotransmitter receptor gene dysregulation during the progression of Alzheimer's disease

Pretangle pathology within cholinergic nucleus basalis neurons coincides with neurotrophic and neurotransmitter receptor gene dysregulation during the progression of Alzheimer's disease

Nerve Growth Factor Helps Protect Retina in Experimental Retinal Detachment

The neurotrophin receptor p75 regulates gustatory axon branching and promotes innervation of the tongue during development

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