Effects of proNGF on Neuronal Viability, Neurite Growth and Amyloid-beta Metabolism

Wang, Yanjiang; Valadares, Deborah; Sun, Ying; Wang, Xin; Zhong, Jin‐Hua; Liu, Xiaohong; Majd, Shohreh; Chen, Li; Gao, Chang-Yue; Chen, Si; Lim, Yoon Pin; Pollard, Anthony; Aguilar, Ernest; Gai, Wei-Ping; Yang, Miao; Zhou, Xin‐Fu

doi:10.1007/s12640-009-9098-x

Cited by 31 publications

(20 citation statements)

References 43 publications

(62 reference statements)

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“…For primary cortical neuron cultures, p75NTR +/+ ( n = 12), p75NTR −/− ( n = 6) mice postnatal day 1 (P1) were killed, neurons were purified as described previously [11], [65]. Briefly, cortices were collected, meninges removed and tissue sliced into 0.5 mm pieces.…”

Section: Methodsmentioning

confidence: 99%

ProBDNF Collapses Neurite Outgrowth of Primary Neurons by Activating RhoA

et al. 2012

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BackgroundNeurons extend their dendrites and axons to build functional neural circuits, which are regulated by both positive and negative signals during development. Brain-derived neurotrophic factor (BDNF) is a positive regulator for neurite outgrowth and neuronal survival but the functions of its precursor (proBDNF) are less characterized.Methodology/Principal FindingsHere we show that proBDNF collapses neurite outgrowth in murine dorsal root ganglion (DRG) neurons and cortical neurons by activating RhoA via the p75 neurotrophin receptor (p75NTR). We demonstrated that the receptor proteins for proBDNF, p75NTR and sortilin, were highly expressed in cultured DRG or cortical neurons. ProBDNF caused a dramatic neurite collapse in a dose-dependent manner and this effect was about 500 fold more potent than myelin-associated glycoprotein. Neutralization of endogenous proBDNF by using antibodies enhanced neurite outgrowth in vitro and in vivo, but this effect was lost in p75NTR−/− mice. The neurite outgrowth of cortical neurons from p75NTR deficient (p75NTR−/−) mice was insensitive to proBDNF. There was a time-dependent reduction of length and number of filopodia in response to proBDNF which was accompanied with a polarized RhoA activation in growth cones. Moreover, proBDNF treatment of cortical neurons resulted in a time-dependent activation of RhoA but not Cdc42 and the effect was absent in p75NTR−/− neurons. Rho kinase (ROCK) and the collapsin response mediator protein-2 (CRMP-2) were also involved in the proBDNF action.ConclusionsproBDNF has an opposing role in neurite outgrowth to that of mature BDNF. Our observations suggest that proBDNF collapses neurites outgrowth and filopodial growth cones by activating RhoA through the p75NTR signaling pathway.

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Section: Methodsmentioning

confidence: 99%

ProBDNF Collapses Neurite Outgrowth of Primary Neurons by Activating RhoA

et al. 2012

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“…Moreover, evidence indicate that pro-NGF inhibit the proliferation and differentiation of hippocampal neural stem or progenitor cells from postnatal mice [62]. These effects of pro-NGF might be mediated through p75NTR [63] (Figure 2). In this context, a study performed by Al-Shawi et al (2008) indicated that proNGF leads cell death in basal forebrain and peripheral sympathetic neurons of old rat.…”

Section: Ngf and Agingmentioning

confidence: 98%

The involvement of BDNF, NGF and GDNF in aging and Alzheimer's disease

Budni¹,

Bellettini-Santos²,

Mina³

et al. 2015

Aging and disease

331

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Aging is a normal physiological process accompanied by cognitive decline. This aging process has been the primary risk factor for development of aging-related diseases such as Alzheimer's disease (AD). Cognitive deficit is related to alterations of neurotrophic factors level such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and glial cellderived neurotrophic factor (GDNF). These strong relationship between aging and AD is important to investigate the time which they overlap, as well as, the pathophysiological mechanism in each event. Considering that aging and AD are related to cognitive impairment, here we discuss the involving these neurotrophic factors in the aging process and AD.

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“…The proforms of neurotrophins such as proNGF and proBDNF, preferentially bind to p75NTR-sortilin receptor whereas mature neurotrophins are preferred ligands for Trk receptors. While signals emanating from Trks support neuronal survival, cell growth and synaptic strengthening, the proNGF-p75NTR-sortilin signaling can induce apoptosis, attenuate growth and weaken synaptic signaling [15–22]. Accumulating evidences have indicated that p75NTR-sortilin signaling triggered by abnormality or imbalance of proNGF/NGF might be involved in the glial-neuronal interaction, degenerative loss of motor neurons or cholinergic neurons, disease onset or progression in AD, PD and ALS [9–14].…”

Section: Introductionmentioning

confidence: 99%

LPS-Induced proNGF Synthesis and Release in the N9 and BV2 Microglial Cells: A New Pathway Underling Microglial Toxicity in Neuroinflammation

et al. 2013

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PurposeWhile aberrant activation of microglial cells was evidently involved in neuroinflammation and neurotoxicity in the neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, objective of study was to address if activated microglias deliver their effect by releasing pro-neurotrophins.Materials and methodsBy in vitro culture of N9 and BV2 cell lines and lipopolysaccharide (LPS) stimulation model, generation and release of proNGF, proBDNF and MMP-9 was studied in the activated microglial cells by immunocytochemistry, western blotting and bioassay methods.ResultsActivation of microglial cells was observed with obvious increasing iba1-immunoreactivity following LPS stimulation in cell culture. Synthesis and up-regulation of proNGF protein significantly occurred in N9 and BV2 cells 12h-48h after LPS exposure, whereas no significant changes of proBDNF and MMP9 were observed in these microglial cell lines with LPS insult. More interestingly, extracellular release or secretion of proNGF molecule was also detected in culture medium of N9 cells after LPS stimulation. Finally, bioassay using MTT, Hoechst/PI and TUNEL staining in SH-SY5Y cells further confirmed that proNGF treatment could result in apoptotic cell death but it did not significantly influence cell viability of SH-SY5Y cells.ConclusionsThis in vitro study revealed LPS-stimulated proNGF synthesis and release in activated N9/BV2 microglial cell lines, also suggesting that proNGF may appeal a new pathway or possible mechanism underlying microglial toxicity in the neuroinflammation and a potential target for therapeutic manipulation of the neurodegenerative diseases.

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Effects of proNGF on Neuronal Viability, Neurite Growth and Amyloid-beta Metabolism

Cited by 31 publications

References 43 publications

ProBDNF Collapses Neurite Outgrowth of Primary Neurons by Activating RhoA

ProBDNF Collapses Neurite Outgrowth of Primary Neurons by Activating RhoA

The involvement of BDNF, NGF and GDNF in aging and Alzheimer's disease

LPS-Induced proNGF Synthesis and Release in the N9 and BV2 Microglial Cells: A New Pathway Underling Microglial Toxicity in Neuroinflammation

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