scholarly journals Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tao Yang ◽  
Kevin C. Tran ◽  
Anne Y. Zeng ◽  
Stephen M. Massa ◽  
Frank M. Longo
Keyword(s):  
Small Molecule ◽  
Intracellular Signaling ◽  
Rho Kinase ◽  
Tau Phosphorylation ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Fyn Kinase ◽  
Synapse Degeneration ◽  
Preclinical And Clinical Studies

AbstractLongitudinal preclinical and clinical studies suggest that Aβ drives neurite and synapse degeneration through an array of tau-dependent and independent mechanisms. The intracellular signaling networks regulated by the p75 neurotrophin receptor (p75NTR) substantially overlap with those linked to Aβ and to tau. Here we examine the hypothesis that modulation of p75NTR will suppress the generation of multiple potentially pathogenic tau species and related signaling to protect dendritic spines and processes from Aβ-induced injury. In neurons exposed to oligomeric Aβ in vitro and APP mutant mouse models, modulation of p75NTR signaling using the small-molecule LM11A-31 was found to inhibit Aβ-associated degeneration of neurites and spines; and tau phosphorylation, cleavage, oligomerization and missorting. In line with these effects on tau, LM11A-31 inhibited excess activation of Fyn kinase and its targets, tau and NMDA-NR2B, and decreased Rho kinase signaling changes and downstream aberrant cofilin phosphorylation. In vitro studies with pseudohyperphosphorylated tau and constitutively active RhoA revealed that LM11A-31 likely acts principally upstream of tau phosphorylation, and has effects preventing spine loss both up and downstream of RhoA activation. These findings support the hypothesis that modulation of p75NTR signaling inhibits a broad spectrum of Aβ-triggered, tau-related molecular pathology thereby contributing to synaptic resilience.

scholarly journals Isoflurane Neurotoxicity Is Mediated by p75NTR-RhoA Activation and Actin Depolymerization

2011 ◽  
Vol 114 (1) ◽  
pp. 49-57 ◽  
Author(s):  
Brian P. Lemkuil ◽  
Brian P. Head ◽  
Matthew L. Pearn ◽  
Hemal H. Patel ◽  
John C. Drummond ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Hippocampal Slice ◽  
Hippocampal Slices ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Actin Depolymerization ◽  
Rhoa Activation ◽  
Hippocampal Slice Cultures ◽  
Developing Neurons

Background The mechanisms by which isoflurane injured the developing brain are not clear. Recent work has demonstrated that it is mediated in part by activation of p75 neurotrophin receptor. This receptor activates RhoA, a small guanosine triphosphatase that can depolymerize actin. It is therefore conceivable that inhibition of RhoA or prevention of cytoskeletal depolymerization might attenuate isoflurane neurotoxicity. This study was conducted to test these hypotheses using primary cultured neurons and hippocampal slice cultures from neonatal mouse pups. Methods Primary neuron cultures (days in vitro, 4-7) and hippocampal slice cultures from postnatal day 4-7 mice were exposed to 1.4% isoflurane (4 h). Neurons were pretreated with TAT-Pep5, an intracellular inhibitor of p75 neurotrophin receptor, the cytoskeletal stabilizer jasplakinolide, or their corresponding vehicles. Hippocampal slice cultures were pretreated with TAT-Pep5 before isoflurane exposure. RhoA activation was evaluated by immunoblot. Cytoskeletal depolymerization and apoptosis were evaluated with immunofluorescence microscopy using drebrin and cleaved caspase-3 staining, respectively. Results RhoA activation was increased after 30 and 120 min of isoflurane exposure in neurons; TAT-Pep5 (10 μm) decreased isoflurane-mediated RhoA activation at both time intervals. Isoflurane decreased drebrin immunofluorescence and enhanced cleaved caspase-3 in neurons, effects that were attenuated by pretreatment with either jasplakinolide (1 μm) or TAT-Pep5. TAT-Pep5 attenuated the isoflurane-mediated decrease in phalloidin immunofluorescence. TAT-Pep5 significantly attenuated isoflurane-mediated loss of drebrin immunofluorescence in hippocampal slices. Conclusions Isoflurane results in RhoA activation, cytoskeletal depolymerization, and apoptosis. Inhibition of RhoA activation or prevention of downstream actin depolymerization significantly attenuated isoflurane-mediated neurotoxicity in developing neurons.

scholarly journals proBDNF expression induces apoptosis and inhibits synaptic regeneration by regulating the RhoA-JNK pathway in an in vitro post-stroke depression model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bangkun Yang ◽  
Lesheng Wang ◽  
Ying Nie ◽  
Wei Wei ◽  
Wenping Xiong
Keyword(s):  
Neural Plasticity ◽  
Cell Model ◽  
Neurotrophin Receptor ◽  
Control Group ◽  
P75 Neurotrophin Receptor ◽  
Post Stroke ◽  
Post Stroke Depression ◽  
Cellular Apoptosis ◽  
Related Proteins

AbstractBrain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of post-stroke depression (PSD). However, the precise function and potential mechanism of proBDNF, the precursor form of BDNF, are unknown. In our study, a PSD-like model was established by treating neuronal cells with oxygen-glucose deprivation and corticosterone. We found that the protein proBDNF levels were significantly higher in the cortex and hippocampus in the PSD group than in the control group, suggesting that proBDNF plays a role in the pathophysiology of PSD. Furthermore, we re-established the PSD-like cell model using recombinant p75 neurotrophin receptor (p75NTR) or silencing c-Jun N-terminal kinase (JNK), and found that the PSD-induced upregulation of proBDNF was inhibited by recombinant p75NTR and JNK silencing (siJNK), and increased cellular apoptosis. Moreover, the application of recombinant p75NTR and siJNK in the PSD-like cell model significantly reversed the expression of apoptosis-related and depression-related proteins and decreased cellular apoptosis. Our findings suggest that proBDNF is involved in neural plasticity in PSD in vitro. The RhoA-JNK signaling pathway is activated after proBDNF binds to the p75NTR receptor, followed by the expression of apoptosis-related proteins (PSD95, synaptophysin, and P-cofilin), which contribute to PSD progression. The mechanism might involve the promotion of cellular apoptosis and the inhibition of nerve synapses regeneration by proBDNF.

scholarly journals The p75 Neurotrophin Receptor Promotes Amyloid- (1-42)-Induced Neuritic Dystrophy In Vitro and In Vivo

2009 ◽  
Vol 29 (34) ◽  
pp. 10627-10637 ◽  
Author(s):  
J. K. Knowles ◽  
J. Rajadas ◽  
T.-V. V. Nguyen ◽  
T. Yang ◽  
M. C. LeMieux ◽  
...  
Keyword(s):  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Neuritic Dystrophy

scholarly journals Post-stroke administration of the p75 neurotrophin receptor modulator, LM11A-31, attenuates chronic changes in brain metabolism, increases neurotransmitter levels, and improves recovery

2021 ◽  
Author(s):  
Thuy-Vi V. Nguyen ◽  
Rachael H. Crumpacker ◽  
Kylie E. Calderon ◽  
Frankie G. Garcia ◽  
Jacob C. Zbesko ◽  
...  
Keyword(s):  
Small Molecule ◽  
Cognitive Abilities ◽  
Immune Cell ◽  
Principal Component ◽  
Stroke Recovery ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Ipsilateral Hemisphere ◽  
Chronic Inflammatory Response ◽  
Post Stroke

ABSTRACTThe aim of this study was to test whether post-stroke oral administration of a small molecule p75 neurotrophin receptor (p75NTR) modulator (LM11A-31) can augment neuronal survival and improve recovery in a mouse model of stroke. Mice were administered LM11A-31 for up to 12 weeks, beginning 1 week after stroke. Metabolomic analysis revealed that after 2 weeks of daily treatment, mice that received LM11A-31 were distinct from vehicle treated mice by principal component analysis, and had higher levels of glutamate, serotonin, acetylcholine, and dopamine in their ipsilateral hemisphere. LM11A-31 treatment also improved redox homeostasis by restoring reduced glutathione. It also offset a stroke induced reduction in glycolysis by increasing acetyl-CoA. There was no effect on cytokine levels in the infarct. At 13 weeks following stroke, adaptive immune cell infiltration in the infarct was unchanged in LM11A-31 treated mice, indicating that LM11A-31 does not alter the chronic inflammatory response to stroke at the site of the infarct. However, LM11A-31 treated mice had less brain atrophy, neurodegeneration, tau pathology, and microglial activation in other regions of the ipsilateral hemisphere. These findings correlated with improved recovery of motor function on a ladder test, improved sensorimotor and cognitive abilities on a nesting test, and less impulsivity in an open field test. These data support small molecule modulation of the p75 neurotrophin receptor for preserving neuronal health and function during stroke recovery.SIGNIFICANCE STATEMENTThe findings from this study introduce the p75 neurotrophin receptor as a novel small molecule target for promotion of stroke recovery. Given that LM11A-31 is in clinical trials as a potential therapy for Alzheimer’s disease, it could be considered as a candidate for assessment in stroke or vascular dementia studies.

scholarly journals Propofol Neurotoxicity Is Mediated by p75 Neurotrophin Receptor Activation

2012 ◽  
Vol 116 (2) ◽  
pp. 352-361 ◽  
Author(s):  
Matthew L. Pearn ◽  
Yue Hu ◽  
Ingrid R. Niesman ◽  
Hemal H. Patel ◽  
John C. Drummond ◽  
...  
Keyword(s):  
Green Fluorescent Protein ◽  
Fluorescent Protein ◽  
Receptor Activation ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Wild Type ◽  
P75 Ntr ◽  
Green Fluorescent ◽  
Developing Neurons

Background Propofol exposure to neurons during synaptogenesis results in apoptosis, leading to cognitive dysfunction in adulthood. Previous work from our laboratory showed that isoflurane neurotoxicity occurs through p75 neurotrophin receptor (p75(NTR)) and subsequent cytoskeleton depolymerization. Given that isoflurane and propofol both suppress neuronal activity, we hypothesized that propofol also induces apoptosis in developing neurons through p75(NTR). Methods Days in vitro 5-7 neurons were exposed to propofol (3 μM) for 6 h and apoptosis was assessed by cleaved caspase-3 (Cl-Csp3) immunoblot and immunofluorescence microscopy. Primary neurons from p75(NTR-/-) mice or wild-type neurons were treated with propofol, with or without pretreatment with TAT-Pep5 (10 μM, 15 min), a specific p75(NTR) inhibitor. P75(NTR-/-) neurons were transfected for 72 h with a lentiviral vector containing the synapsin-driven p75(NTR) gene (Syn-p75(NTR)) or control vector (Syn-green fluorescent protein) before propofol. To confirm our in vitro findings, wild-type mice and p75(NTR-/-) mice (PND5) were pretreated with either TAT-Pep5 or TAT-ctrl followed by propofol for 6 h. Results Neurons exposed to propofol showed a significant increase in Cl-Csp3, an effect attenuated by TAT-Pep5 and hydroxyfasudil. Apoptosis was significantly attenuated in p75(NTR-/-) neurons. In p75(NTR-/-) neurons transfected with Syn-p75(NTR), propofol significantly increased Cl-Csp3 in comparison with Syn-green fluorescent protein-transfected p75(NTR-/-) neurons. Wild-type mice exposed to propofol exhibited increased Cl-Csp3 in the hippocampus, an effect attenuated by TAT-Pep5. By contrast, propofol did not induce apoptosis in p75(NTR-/-) mice. Conclusion These results demonstrate that propofol induces apoptosis in developing neurons in vivo and in vitro and implicate a role for p75(NTR) and the downstream effector RhoA kinase.

scholarly journals Heterogeneous ventricular sympathetic innervation, altered β-adrenergic receptor expression, and rhythm instability in mice lacking the p75 neurotrophin receptor

2010 ◽  
Vol 298 (6) ◽  
pp. H1652-H1660 ◽  
Author(s):  
Christina U. Lorentz ◽  
Eric N. Alston ◽  
Todd Belcik ◽  
Jonathan R. Lindner ◽  
George D. Giraud ◽  
...  
Keyword(s):  
Adrenergic Receptor ◽  
Sympathetic Neurons ◽  
Sympathetic Innervation ◽  
Sympathetic Nerves ◽  
Nerve Fibers ◽  
Receptor Expression ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Semaphorin 3A

Sympathetic nerves stimulate cardiac function through the release of norepinephrine and the activation of cardiac β1-adrenergic receptors. The sympathetic innervation of the heart is sculpted during development by chemoattractive factors including nerve growth factor (NGF) and the chemorepulsive factor semaphorin 3a. NGF acts through the TrkA receptor and the p75 neurotrophin receptor (p75NTR) in sympathetic neurons. NGF stimulates sympathetic axon extension into the heart through TrkA, but p75NTR modulates multiple coreceptors that can either stimulate or inhibit axon outgrowth. In mice lacking p75NTR, the sympathetic innervation density in target tissues ranges from denervation to hyperinnervation. Recent studies have revealed significant changes in the sympathetic innervation density of p75NTR-deficient (p75NTR−/−) atria between early postnatal development and adulthood. We examined the innervation of adult p75NTR−/− ventricles and discovered that the subendocardium of the p75NTR−/− left ventricle was essentially devoid of sympathetic nerve fibers, whereas the innervation density of the subepicardium was normal. This phenotype is similar to that seen in mice overexpressing semaphorin 3a, and we found that sympathetic axons lacking p75NTR are more sensitive to semaphorin 3a in vitro than control neurons. The lack of subendocardial innervation was associated with decreased dP/d t, altered cardiac β1-adrenergic receptor expression and sensitivity, and a significant increase in spontaneous ventricular arrhythmias. The lack of p75NTR also resulted in increased tyrosine hydroxylase content in cardiac sympathetic neurons and elevated norepinephrine in the right ventricle, where innervation density was normal.

scholarly journals Astaxanthin Ameliorates Ischemic-Hypoxic-Induced Neurotrophin Receptor p75 Upregulation in the Endothelial Cells of Neonatal Mouse Brains

2019 ◽  
Vol 20 (24) ◽  
pp. 6168
Author(s):  
Min-Hsun Kuo ◽  
Hung-Fu Lee ◽  
Yi-Fang Tu ◽  
Li-Hsuan Lin ◽  
Ya-Yun Cheng ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Reperfusion Injury ◽  
Cell Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor

Ischemic stroke is a leading cause of human death in present times. Two phases of pathological impact occur during an ischemic stroke, namely, ischemia and reperfusion. Both periods include individual characteristic effects on cell injury and apoptosis. Moreover, these conditions can cause severe cell defects and harm the blood-brain barrier (BBB). Also, the BBB components are the major targets in ischemia-reperfusion injury. The BBB owes its enhanced protective roles to capillary endothelial cells, which maintain BBB permeability. One of the nerve growth factor (NGF) receptors initiating cell signaling, once activated, is the p75 neurotrophin receptor (p75NTR). This receptor is involved in both the survival and apoptosis of neurons. Although many studies have attempted to explain the role of p75NTR in neurons, the mechanisms in endothelial cells remain unclear. Endothelial cells are the first cells to encounter p75NTR stimuli. In this study, we found the upregulated p75NTR expression and reductive expression of tight junction proteins after in vivo and in vitro ischemia-reperfusion injury. Moreover, astaxanthin (AXT), an antioxidant drug, was utilized and was found to reduce p75NTR expression and the number of apoptotic cells. This study verified that p75NTR plays a prominent role in endothelial cell death and provides a novel downstream target for AXT.

scholarly journals Structural and functional elucidation of NF-κB signaling by the p75 neurotrophin receptor through recruitment of TRADD

2021 ◽  
Author(s):  
Ning Zhang ◽  
Lilian Kisiswa ◽  
Ajeena Ramanujan ◽  
Zhen Li ◽  
Eunice Weiling Sim ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Neurotrophin Receptor ◽  
Structural Basis ◽  
P75 Neurotrophin Receptor ◽  
Death Domain ◽  
Structural Mechanism ◽  
Downstream Signaling ◽  
Developing Neurons

Abstractp75 neurotrophin receptor (p75NTR) is a critical mediator of neuronal death and tissue remodeling and has been implicated in various neurodegenerative diseases. The death domain (DD) of p75NTR is an intracellular signaling hub and has been shown to interact with diverse adaptor proteins. However, the structural mechanism and physiological relevance of the adaptor protein TRADD in neuronal p75NTR signaling remain poorly understood. Here we report an NMR structure of the complex between p75NTR-DD and TRADD-DD and elucidate the structural basis of specific DD recognition in the p75NTR/TRADD signaling pathway. Furthermore, we identify spatiotemporal overlap of p75NTR and TRADD expression in developing cerebellar granule neurons (CGNs) at early postnatal stages and reveal the functional role of TRADD recruitment to p75NTR in the regulation of canonical NF-κB signaling and cell survival in CGNs. Our results provide a new structural framework for understanding how the recruitment of TRADD to p75NTR through DD interactions creates a membrane-proximal platform to propagate downstream signaling in developing neurons.

240 DEVELOPMENT, DIFFERENTIATION, AND Trk EXPRESSION IN PARTHENOGENETIC BOVINE BLASTOCYSTS

2008 ◽  
Vol 20 (1) ◽  
pp. 199
Author(s):  
J. N. Caamaño ◽  
M. Muñoz ◽  
M. Álvarez-Viejo ◽  
C. Díez ◽  
C. de Frutos ◽  
...  
Keyword(s):  
Inner Cell Mass ◽  
Cell Mass ◽  
Embryonic Stem ◽  
Neurotrophin Receptor ◽  
Positive Staining ◽  
P75 Neurotrophin Receptor ◽  
Blastocyst Development ◽  
Surface Receptors ◽  
Parthenogenetic Embryos

Parthenogenetic embryos allow study of the roles of paternal and maternal genomes in early mammalian development. Nevertheless, pregnancies established with parthenotes arrest around 48 days. Genomic imprinting alterations, fewer cells, and apoptotic index are higher in parthenotes than in IVF embryos and are likely to contribute to the failure to reach full-term development. Neurotrophins are a family of anti-apoptotic cytokines that mediate survival, growth, and differentiation by binding to two types of cell surface receptors, tyrosine kinase (Trk) and the low affinity p75 neurotrophin receptor (p75). Trk and p75 receptors have been localized in early bovine in vitro-produced embryos. At present there are no available data on expression of Trk and numbers of cells in the inner cell mass (ICM) and the trophectoderm (TE) of parthenogenetic embryos. The aim of this study was to evaluate the quality of bovine parthenotes in terms of cell allocation and blastocyst development, and to analyze TrkA, TrkB, and TrKC expression in the ICM and TE. Starting from in vitro-matured slaughterhouse oocytes, embryos were produced by conventional IVF, while parthenotes resulted from ionomycin activation followed by 6-dimethylaminopurine. Zygotes were cultured in SOF + 6 gL– 1 BSA. In vitro development was assessed for IVF embryos on (and referred to on) Days 3, 6, 7, and 8 after fertilization, and 24 h before these time points for parthenotes. Data were analyzed by the GLM procedure of SAS SAS Institute, Inc., Cary, NC, USA). Parthenotes cleaved at rates similar to IVF embryos (80.8 � 3.9 v. 85.8 � 3.9, respectively), but percentages of 5–8 and 8–16 cell stages were lower in parthenotes (40.4 � 4.3 v. 67.9 � 4.3, P < 0.005, and 9.7 � 3.5 v. 25.3 � 3.5, P < 0.01, respectively). However, parthenogenetic blastocyst rates were higher than those in IVF embryos (Day 6: 33.6 � 2.6 v. 11.0 � 2.6, P < 0.005; Day 7: 49.2 � 4.1 v. 30.0 � 4.1, P < 0.02). Double staining showed fewer TE cells in parthenotes (78.7 � 8.5) than in IVF embryos (111.0 � 8.6, P < 0.02). This reduction accounted for a reduced number of total cells in parthenotes (105.3 � 9.9) v. controls (144.0 � 9.8, P < 0.01), while numbers of cells in the ICM were comparable (27.9 � 3.5 v. 31.1 � 3.5, in parthenotes and controls, respectively). As in the case of IVF embryos, immunocytochemical analysis showed positive staining for Trk receptors in parthenotes. Although parthenotes showed blastocyst development rates higher than in IVF embryos, the reduced amount of TE cells in parthenotes could negatively affect implantation. Interestingly, parthenotes do not contain abnormally reduced cell numbers in their ICM, and they express Trks. Therefore, specific stimulation of these receptors with appropriate cytokines could improve blastocyst development and embryonic stem cell derivation. This work was supported by the Spanish Ministry of Science and Education (AGL2005-04479). Dr. Muñoz was supported by FICYT.

Sign in / Sign up

Export Citation Format

Share Document