Involvement of p75NTR in the alteration of neuronal network activity by Aβ

2019 ◽  
Author(s):  
hucheng zhao
Keyword(s):  
Neuronal Network ◽  
Hippocampal Neurons ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Network Activity ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Neuronal Viability ◽  
Neuronal Network Activity ◽  
Low Concentrations

Abstract Background：The aberrant accumulation of amyloid-beta (Aβ) in the neocortex and hippocampus is one of the initial causes of Alzheimer's disease (AD). The p75 neurotrophin receptor (p75NTR) has been proposed to mediate Aβ-induced neuronal cell death. Whether p75NTR is required for the effects of Aβ on neuronal network activity，remains unclear. Results: Our results show that low concentrations of Aβ42 did not affect neuronal viability and synapse number. However, the Aβ42 treatment decreased the neuronal network activity of cultured wild-type hippocampal neurons, including a significant decrease of Ca2+ oscillations, spontaneous postsynaptic activity and synaptic connectivity. Moreover, the Aβ42 treatment did not affect the neuronal network activity of Tg2576/p75NTR+/− and p75NTR+/− hippocampal neurons. Conclusion: These studies will shed new light on the pathogenesis of AD and aid the development of related drugs.

scholarly journals Xenon Neurotoxicity in Rat Hippocampal Slice Cultures Is Similar to Isoflurane and Sevoflurane

2013 ◽  
Vol 119 (2) ◽  
pp. 335-344 ◽  
Author(s):  
Heather Brosnan ◽  
Philip E. Bickler
Keyword(s):  
Cell Death ◽  
Hippocampal Neurons ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neuron Death ◽  
Neuroprotective Effects ◽  
Low Concentrations ◽  
Vitro Model ◽  
Developing Neurons

Abstract Background: Anesthetic neurotoxicity in the developing brain of rodents and primates has raised concern. Xenon may be a nonneurotoxic alternative to halogenated anesthetics, but its toxicity has only been studied at low concentrations, where neuroprotective effects predominate in animal models. An equipotent comparison of xenon and halogenated anesthetics with respect to neurotoxicity in developing neurons has not been made. Methods: Organotypic hippocampal cultures from 7-day-old rats were exposed to 0.75, 1, and 2 minimum alveolar concentrations (MAC) partial pressures (60% xenon at 1.2, 2.67, and 3.67 atm; isoflurane at 1.4, 1.9, and 3.8%; and sevoflurane at 3.4 and 6.8%) for 6 h, at atmospheric pressure or in a pressure chamber. Cell death was assessed 24 h later with fluorojade and fluorescent dye exclusion techniques. Results: Xenon caused death of hippocampal neurons in CA1, CA3, and dentate regions after 1 and 2 MAC exposures, but not at 0.75 MAC. At 1 MAC, xenon increased cell death 40% above baseline (P < 0.01; ANOVA with Dunnett test). Both isoflurane and sevoflurane increased neuron death at 1 but not 2 MAC. At 1 MAC, the increase in cell death compared with controls was 63% with isoflurane and 90% with sevoflurane (both P < 0.001). Pretreatment of cultures with isoflurane (0.75 MAC) reduced neuron death after 1 MAC xenon, isoflurane, and sevoflurane. Conclusion: Xenon causes neuronal cell death in an in vitro model of the developing rodent brain at 1 MAC, as does isoflurane and sevoflurane at similarly potent concentrations. Preconditioning with a subtoxic dose of isoflurane eliminates this toxicity.

scholarly journals Astrocytes Protect against Isoflurane Neurotoxicity by Buffering pro-brain–derived Neurotrophic Factor

2015 ◽  
Vol 123 (4) ◽  
pp. 810-819 ◽  
Author(s):  
Creed M. Stary ◽  
Xiaoyun Sun ◽  
Rona G. Giffard
Keyword(s):  
Cell Death ◽  
Neurotrophic Factor ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Brain Derived Neurotrophic Factor ◽  
Neurotrophin Receptor ◽  
Enzyme Linked Immunosorbent Assay ◽  
Neuronal Cultures ◽  
P75 Neurotrophin Receptor ◽  
Primary Neuronal Cultures

Abstract Background: Isoflurane induces cell death in neurons undergoing synaptogenesis via increased production of pro-brain–derived neurotrophic factor (proBDNF) and activation of postsynaptic p75 neurotrophin receptor (p75NTR). Astrocytes express p75NTR, but their role in neuronal p75NTR-mediated cell death remains unclear. The authors investigated whether astrocytes have the capacity to buffer increases in proBDNF and protect against isoflurane/p75NTR neurotoxicity. Methods: Cell death was assessed in day in vitro (DIV) 7 mouse primary neuronal cultures alone or in co-culture with age-matched or DIV 21 astrocytes with propidium iodide 24 h after 1 h exposure to 2% isoflurane or recombinant proBDNF. Astrocyte-targeted knockdown of p75NTR in co-culture was achieved with small-interfering RNA and astrocyte-specific transfection reagent and verified with immunofluorescence microscopy. proBDNF levels were assessed by enzyme-linked immunosorbent assay. Each experiment used six to eight replicate cultures/condition and was repeated at least three times. Results: Exposure to isoflurane significantly (P < 0.05) increased neuronal cell death in primary neuronal cultures (1.5 ± 0.7 fold, mean ± SD) but not in co-culture with DIV 7 (1.0 ± 0.5 fold) or DIV 21 astrocytes (1.2 ± 1.2 fold). Exogenous proBDNF dose dependently induced neuronal cell death in both primary neuronal and co-cultures, an effect enhanced by astrocyte p75NTR inhibition. Astrocyte-targeted p75NTR knockdown in co-cultures increased media proBDNF (1.2 ± 0.1 fold) and augmented isoflurane-induced neuronal cell death (3.8 ± 3.1 fold). Conclusions: The presence of astrocytes provides protection to growing neurons by buffering increased levels of proBDNF induced by isoflurane. These findings may hold clinical significance for the neonatal and injured brain where increased levels of proBDNF impair neurogenesis.

scholarly journals Natural LXRβ agonist stigmasterol confers protection against excitotoxicity after hypoxia- reoxygenation (H/R) injury via regulation of mitophagy in primary hippocampal neurons

2019 ◽  
Author(s):  
Md. Nazmul Haque ◽  
Md. Abdul Hannan ◽  
Raju Dash ◽  
Il Soo Moon
Keyword(s):  
Hippocampal Neurons ◽  
Neuroprotective Effect ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Adaptor Protein ◽  
Drug Candidate ◽  
Hippocampal Culture ◽  
Excitatory Neurotransmitter ◽  
Neuronal Viability ◽  
Hypoxia Reoxygenation

AbstractIschemic brain injury represents insufficient oxygen supply to the brain and further damage occurs upon reoxygenation due to elevated intracellular levels excitatory neurotransmitter glutamate and subsequent production of reactive oxygen species (ROS) which has long been related to neuronal cell death of hippocampus brain region. Previously, using cell biological assay and transcriptomics analysis we reported that naturally occurring phytosterol Stigmasterol (ST) promotes brain development and function through the enhancement of neuronal cytoarchitectural complexity and functional maturation in rat hippocampal neurons by induction of immediate early genes (IEGs). In the present study we investigated the STs role in neuroprotection and found that ST also dose-dependently increased the neuronal viability in hypoxia reoxygenation (H/R) induced injury at hippocampal culture. ST, at an optimal concentration of 20 μM, significantly reduced the transport of vesicular glutamate (VGULT1), synaptic vesicle pool size, expression of GluN2B, rate of ROS formation (DCFDA) but restore mitochondrial membrane potential (JC1) and DNA fragmentation (H2AX) against H/R induced injury. More interestingly, ST also significantly induces the expression of autophagy marker protein LC3BII and the adaptor protein P62 but not HSC70 which indicates STs capability of induction of chaperon independent autophagy at H/R treated cultures. Furthermore densitometric analysis reveals ST also significantly increases PINK1 (PTEN induced protein kinase 1) expression therefore, indicates its role in mitophagy. In addition, molecular dynamic simulations study indicates that ST bind to LXRβ and forms hydrogen bonds with ASN239, GLU281, ARG319, THR316, SER278, ASN239 and SER278 residues at high occupancy with GLU281(20.21%) and ARG319 (21.04%,) residues, which is necessary for sterol binding to the LXRβ. Taken together these findings suggest that neuroprotective effect of ST might be associated with anti-excitatory and anti-oxidative actions on CNS neurons and could be a promising drug candidate for the treatment or prevention of ischemic stroke related neurological disorders.

scholarly journals Evidence for the equilibrium between monomers and dimers of the death domain of the p75 neurotrophin receptor

2021 ◽  
Author(s):  
Zhen Li ◽  
Zhi Lin ◽  
Carlos F. Ibanez
Keyword(s):  
Room Temperature ◽  
Molecular Mechanisms ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Size Exclusion ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Death Domain ◽  
Nmr Studies ◽  
Activation Mechanisms

The p75 neurotrophin receptor (p75NTR) is an important mediator of synaptic depression and neuronal cell death, and its expression increases upon nerve injury and in neurodegenerative diseases. However, the molecular mechanisms leading to the activation of this receptor are still a matter of debate. The oligomerization properties of the death domain (DD) of p75NTR are critical for our understanding of the activation mechanisms of the receptor. In this paper, we present additional evidence supporting the existence of an equilibrium between monomeric and dimeric forms of the p75NTR DD in solution and in the absence of any other protein. Dynamic light scattering (DLS) measurements of native, untagged human p75NTR DD at room temperature yielded Rh=2.11 for this domain in 20mM phosphate buffer, corresponding to a molecular weight (MW) of approximately 19kDa, much closer to the theoretical MW of the homodimer (i.e. 21kDa) than the monomer. MWs deduced from the Rh of different control proteins used as standards were all congruent with their theoretical MWs. In addition, size-exclusion FPLC profiles of un-tagged human p75NTR DD in both HEPES and phosphate buffers revealed elution volumes corresponding to a MW of about 15kDa, which is intermediate between monomer and dimer, and indicative of dynamic monomer/dimer interconversion during the run. Together with our previous NMR studies, as well as biophysical data for other investigators, these results support the notion that the DD of p75NTR exists in equilibrium between monomers and dimers in solution, a notion that is in agreement with the oligomerization properties of all members of the DD superfamily.

scholarly journals Chopper, a New Death Domain of the p75 Neurotrophin Receptor That Mediates Rapid Neuronal Cell Death

2000 ◽  
Vol 275 (39) ◽  
pp. 30537-30545 ◽  
Author(s):  
Elizabeth J. Coulson ◽  
Kate Reid ◽  
Manuel Baca ◽  
Kylie A. Shipham ◽  
Sarah M. Hulett ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Death Domain

scholarly journals p75 Neurotrophin Receptor Mediates Neuronal Cell Death by Activating GIRK Channels through Phosphatidylinositol 4,5-Bisphosphate

2008 ◽  
Vol 28 (1) ◽  
pp. 315-324 ◽  
Author(s):  
E. J. Coulson ◽  
L. M. May ◽  
S. L. Osborne ◽  
K. Reid ◽  
C. K. Underwood ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Girk Channels

scholarly journals Deletion of LRP1 From Astrocytes Modifies Neuronal Network Activity in an in vitro Model of the Tripartite Synapse

2021 ◽  
Vol 14 ◽  
Author(s):  
Ramona Romeo ◽  
Kristin Glotzbach ◽  
Anja Scheller ◽  
Andreas Faissner
Keyword(s):  
Neuronal Network ◽  
Hippocampal Neurons ◽  
Glutamate Transporter ◽  
Density Lipoprotein ◽  
Precursor Cells ◽  
Network Activity ◽  
Fluorescent Reporter ◽  
Single Action ◽  
Neuronal Network Activity

The low-density lipoprotein receptor-related protein 1 (LRP1) is a transmembrane receptor that binds over 40 potential ligands and is involved in processes such as cell differentiation, proliferation, and survival. LRP1 is ubiquitously expressed in the organism and enriched among others in blood vessels, liver, and the central nervous system (CNS). There, it is strongly expressed by neurons, microglia, immature oligodendrocytes, and astrocytes. The constitutive LRP1 knockout leads to embryonic lethality. Therefore, previous studies focused on conditional LRP1-knockout strategies and revealed that the deletion of LRP1 causes an increased differentiation of neural stem and precursor cells into astrocytes. Furthermore, astrocytic LRP1 is necessary for the degradation of Aβ and the reduced accumulation of amyloid plaques in Alzheimer’s disease. Although the role of LRP1 in neurons has intensely been investigated, the function of LRP1 with regard to the differentiation and maturation of astrocytes and their functionality is still unknown. To address this question, we generated an inducible conditional transgenic mouse model, where LRP1 is specifically deleted from GLAST-positive astrocyte precursor cells. The recombination with resulting knockout events was visualized by the simultaneous expression of the fluorescent reporter tdTomato. We observed a significantly increased number of GLT-1 expressing astrocytes in LRP1-depleted astrocytic cultures in comparison to control astrocytes. Furthermore, we investigated the influence of astrocytic LRP1 on neuronal activity and synaptogenesis using the co-culture of hippocampal neurons with control or LRP1-depleted astrocytes. These analyses revealed that the LRP1-deficient astrocytes caused a decreased number of single action potentials as well as a negatively influenced neuronal network activity. Moreover, the proportion of pre- and postsynaptic structures was significantly altered in neurons co-cultured with LPR1-depleted astrocytes. However, the number of structural synapses was not affected. Additionally, the supernatant of hippocampal neurons co-cultured with LRP1-deficient astrocytes showed an altered set of cytokines in comparison to the control condition, which potentially contributed to the altered neuronal transmission and synaptogenesis. Our results suggest astrocytic LRP1 as a modulator of synaptic transmission and synaptogenesis by altering the expression of the glutamate transporter on the cell surface on astrocytes and the release of cytokines in vitro.

Desynchronisation of neuronal network activity in traumatic brain injury

2008 ◽  
Vol 39 (01) ◽  
Author(s):  
F Otto ◽  
J Opatz ◽  
R Hartmann ◽  
D Willbold ◽  
E Donauer ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Network ◽  
Network Activity ◽  
Neuronal Network Activity

Dementia with Lewy bodies—associated ß-synuclein mutations V70M and P123H cause mutation-specific neuropathological lesions

2021 ◽  
Author(s):  
Maryna Psol ◽  
Sofia Guerin Darvas ◽  
Kristian Leite ◽  
Sameehan U Mahajani ◽  
Mathias Bähr ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Sporadic Case ◽  
Network Activity ◽  
Proteinase K ◽  
Neuronal Network Activity ◽  
Distinct Disease

Abstract ß-Synuclein (ß-Syn) has long been considered to be an attenuator for the neuropathological effects caused by the Parkinson’s disease-related α-Synuclein (α-Syn) protein. However, recent studies demonstrated that overabundant ß-Syn can form aggregates and induce neurodegeneration in CNS neurons in vitro and in vivo, albeit at a slower pace as compared to α-Syn. Here we demonstrate that ß-Syn mutants V70M, detected in a sporadic case of Dementia with Lewy Bodies (DLB), and P123H, detected in a familial case of DLB, robustly aggravate the neurotoxic potential of ß-Syn. Intriguingly, the two mutations trigger mutually exclusive pathways. ß-Syn V70M enhances morphological mitochondrial deterioration and degeneration of dopaminergic and non-dopaminergic neurons, but has no influence on neuronal network activity. Conversely, ß-Syn P123H silences neuronal network activity, but does not aggravate neurodegeneration. ß-Syn WT, V70M and P123H formed proteinase K (PK) resistant intracellular fibrils within neurons, albeit with less stable C-termini as compared to α-Syn. Under cell free conditions, ß-Syn V70M demonstrated a much slower pace of fibril formation as compared to WT ß-Syn, and P123H fibrils present with a unique phenotype characterized by large numbers of short, truncated fibrils. Thus, it is possible that V70M and P123H cause structural alterations in ß-Syn, that are linked to their distinct neuropathological profiles. The extent of the lesions caused by these neuropathological profiles is almost identical to that of overabundant α-Syn, and thus likely to be directly involved into etiology of DLB. Over all, this study provides insights into distinct disease mechanisms caused by mutations of ß-Syn.

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