scholarly journals Assessing the therapeutic potential of APPs⍺ in a tau transgenic mouse model of Alzheimers disease

2020 ◽  
Author(s):  
Charlotte Bold ◽  
Danny Baltissen ◽  
Susann Ludewig ◽  
Roman Spilger ◽  
Karl Rohr ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Mouse Model ◽  
Therapeutic Potential ◽  
Large Body ◽  
Transgenic Mouse Model ◽  
Spine Density ◽  
General Applicability ◽  
Plaque Deposition

A large body of evidence indicates a neuroprotective and neurotrophic function for APPs⍺ not only in vitro, but also when expressed by AAV vectors in vivo such as in APP/PS1 transgenic AD model mice with Aβ-induced pathology. Previously, we could show that APPs⍺ rescued deficits of APP/PS1 in synaptic plasticity and spine density and also reduced plaque deposition. Thus, it is crucial to test a more general applicability of APPs⍺ as a treatment for AD and to assess whether APPs⍺ is also beneficial in mice with tau-induced pathology.

scholarly journals Optogenetic Modulation of Cortical Neurons Using Organic Light Emitting Diodes (OLEDs)

2019 ◽  
Author(s):  
Arati Sridharan ◽  
Ankur Shah ◽  
Swathy Sampath Kumar ◽  
James Kyeh ◽  
Joseph Smith ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse ◽  
Cortical Neurons ◽  
Microelectrode Array ◽  
Light Emitting Diodes ◽  
Green Light ◽  
Transgenic Mouse Model ◽  
Light Emitting

ABSTRACTObjectiveThere is a need for low power, scalable photoelectronic devices and systems for emerging optogenetic needs in neuromodulation. Conventional light emitting diodes (LEDs) are constrained by power and lead-counts necessary for scalability. Organic LEDs (OLEDs) offer an exciting approach to decrease power and lead-counts while achieving high channel counts on thin, flexible substrates that conform to brain surfaces or peripheral neuronal fibers. In this study, we investigate the potential for using OLEDs to modulate neuronal networks cultured in vitro on a transparent microelectrode array (MEA) and subsequently validate neurostimulation in vivo in a transgenic mouse model.ApproachCultured mouse cortical neurons were transfected with light-sensitive opsins such as blue-light sensitive channel-rhodopsin (ChR2) and green-light sensitive chimeric channel-rhodopsin (C1V1tt) and stimulated using blue and green OLEDs (with 455 and 520 nm peak emission spectra respectively) at a power of 1 mW/mm2 under pulsed conditions.Main resultsWe demonstrate neuromodulation and optostimulus-locked, single unit-neuronal activity in neurons expressing stimulating and inhibiting opsins (n=4 MEAs, each with 16 recordable channels). We also validated the optostimulus-locked response in a channel-rhodopsin expressing transgenic mouse model, where at least three isolatable single neuronal cortical units respond to OLED stimulation.SignificanceThe above results indicate the feasibility of generating sufficient luminance from OLEDs to perform neuromodulation both in vitro and in vivo. This opens up the possibility of developing thin, flexible OLED films with multiple stimulation sites that can conform to the shape of the neuronal targets in the brain or the peripheral nervous system. However, stability of these OLEDs under chronic conditions still needs to be carefully assessed with appropriate packaging approaches.

scholarly journals EphrinB2-EphB2 signaling for dendrite protection after neuronal ischemia in vivo and oxygen-glucose deprivation in vitro

2020 ◽  
pp. 0271678X2097311
Author(s):  
Zhanyang Yu ◽  
Wenlu Li ◽  
Jing Lan ◽  
Kazuhide Hayakawa ◽  
Xunming Ji ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Mouse Model ◽  
Therapeutic Potential ◽  
Focal Cerebral Ischemia ◽  
Ischemic Injury ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Neuron Soma

In order to rescue neuronal function, neuroprotection should be required not only for the neuron soma but also the dendrites. Here, we propose the hypothesis that ephrin-B2-EphB2 signaling may be involved in dendritic degeneration after ischemic injury. A mouse model of focal cerebral ischemia with middle cerebral artery occlusion (MCAO) method was used for EphB2 signaling test in vivo. Primary cortical neuron culture and oxygen-glucose deprivation were used to assess EphB2 signaling in vitro. siRNA and soluble ephrin-B2 ectodomain were used to block ephrin-B2-Ephb2 signaling. In the mouse model of focal cerebral ischemia and in neurons subjected to oxygen-glucose deprivation, clustering of ephrin-B2 with its receptor EphB2 was detected. Phosphorylation of EphB2 suggested activation of this signaling pathway. RNA silencing of EphB2 prevented neuronal death and preserved dendritic length. To assess therapeutic potential, we compared the soluble EphB2 ectodomain with the NMDA antagonist MK801 in neurons after oxygen-glucose deprivation. Both agents equally reduced lactate dehydrogenase release as a general marker of neurotoxicity. However, only soluble EphB2 ectodomain protected the dendrites. These findings provide a proof of concept that ephrin-B2-EphB2 signaling may represent a novel therapeutic target to protect both the neuron soma as well as dendrites against ischemic injury.

scholarly journals Chronic sodium bromide relieves autistic-like deficits in the Oprm1 mouse model of autism and modulates the activity of serotonin and dopamine receptors in vitro

2020 ◽  
Author(s):  
Cécile Derieux ◽  
Sébastien Roux ◽  
Thierry Plouvier ◽  
Audrey Léauté ◽  
Agathe Brugoux ◽  
...  
Keyword(s):  
Mouse Model ◽  
Dopamine Receptors ◽  
Therapeutic Potential ◽  
Autism Spectrum ◽  
Chloride Ions ◽  
Sodium Bromide ◽  
Bromide Ion ◽  
The Impact

Chronic sodium bromide relieves autistic-like deficits in the Oprm1 mouse model of autism and modulates the activity of serotonin and dopamine receptors in vitro C. DERIEUX 1 , S. ROUX 1 , A. LEAUTE 1 , T. PLOUVIER 2 , J.A.J. BECKER 1 , J. LE MERRER 1 1 Déficits de Récompense, GPCRs et Sociabilité, Physiologie de la Reproduction et des Comportements, INRA UMR0085, CNRS UMR7247, Université de Tours, Inserm ; 37380 Nouzilly, France 2 Térali Innov, 37230 Fondettes, France Corresponding author : [email protected] Autism spectrum disorders (ASD) are complex neurodevelopmental diseases whose diagnosis lies on the detection of impaired social skills together with restricted and repetitive behavior and interests (DSM-5). Although the etiology of ASD remains mostly unknown, impaired excitation/inhibition ratio appears as a common mechanistic feature. Bromide ion is known to reduce hyperexcitability, possibly by competing with chloride ions at channels and transporters and may thus have therapeutic potential in ASD. Aims : We evaluated the therapeutic potential of bromide ion in the Oprm1 -/- mouse model of ASD and the molecular mechanisms involved in bromide treatment, notably effects on GPCRs. Methods : In vivo , we first assessed the effect of chronically administered sodium bromide on autistic-like behavioral deficits and performed RT-qPCR on brain structures known to be involved in ASD. In vitro , we evaluated the impact of bromide ion on G-protein mediated signaling of serotonin and dopamine receptors. Results : In vivo , sodium bromide (30 to 500 mg/Kg) dose-dependently improved social interaction and preference, reduced stereotypies and decreased anxiety. Bromide also impacts the expression of genes coding for some GPCRs, chloride transporters and GABA A subunits. In vitro , bromide behaves as a positive allosteric modulator of 5-HT 6 , 5-HT 7 and D1 receptors but not 5-HT 4 and D2 receptors. Conclusions : The beneficial effects of bromide administration in a genetic murine model of ASD and its impact on both gene expression and GPCR pharmacology predicts high translational potential in patients with autism, despite high heterogeneity in etiology and symptoms.

scholarly journals A bispecific monomeric nanobody induces spike trimer dimers and neutralizes SARS-CoV-2 in vivo

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Leo Hanke ◽  
Hrishikesh Das ◽  
Daniel J. Sheward ◽  
Laura Perez Vidakovics ◽  
Egon Urgard ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Mouse Model ◽  
Therapeutic Potential ◽  
Cell Receptor ◽  
Transgenic Mouse Model ◽  
Viral Antigens ◽  
Host Cell Receptor ◽  
Virus Escape ◽  
Therapeutic Molecules

AbstractAntibodies binding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike have therapeutic promise, but emerging variants show the potential for virus escape. This emphasizes the need for therapeutic molecules with distinct and novel neutralization mechanisms. Here we describe the isolation of a nanobody that interacts simultaneously with two RBDs from different spike trimers of SARS-CoV-2, rapidly inducing the formation of spike trimer–dimers leading to the loss of their ability to attach to the host cell receptor, ACE2. We show that this nanobody potently neutralizes SARS-CoV-2, including the beta and delta variants, and cross-neutralizes SARS-CoV. Furthermore, we demonstrate the therapeutic potential of the nanobody against SARS-CoV-2 and the beta variant in a human ACE2 transgenic mouse model. This naturally elicited bispecific monomeric nanobody establishes an uncommon strategy for potent inactivation of viral antigens and represents a promising antiviral against emerging SARS-CoV-2 variants.

scholarly journals Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Xu Chen ◽  
Yaqiao Li ◽  
Chao Wang ◽  
Yinyan Tang ◽  
Sue-Ann Mok ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse Model ◽  
Autophagic Flux ◽  
Critical Knowledge ◽  
Novel Approach ◽  
Human Neurons ◽  
Lysine Acetyltransferase ◽  
The Relationship

Abstract Background The trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. There is critical knowledge gap in understanding how tau is released and transmitted, and how that is dysregulated in diseases. Previously, we reported that lysine acetyltransferase p300/CBP acetylates tau and regulates its degradation and toxicity. However, whether p300/CBP is involved in regulation of tau secretion and propagation is unknown. Method We investigated the relationship between p300/CBP activity, the autophagy-lysosomal pathway (ALP) and tau secretion in mouse models of tauopathy and in cultured rodent and human neurons. Through a high-through-put compound screen, we identified a new p300 inhibitor that promotes autophagic flux and reduces tau secretion. Using fibril-induced tau spreading models in vitro and in vivo, we examined how p300/CBP regulates tau propagation. Results Increased p300/CBP activity was associated with aberrant accumulation of ALP markers in a tau transgenic mouse model. p300/CBP hyperactivation blocked autophagic flux and increased tau secretion in neurons. Conversely, inhibiting p300/CBP promoted autophagic flux, reduced tau secretion, and reduced tau propagation in fibril-induced tau spreading models in vitro and in vivo. Conclusions We report that p300/CBP, a lysine acetyltransferase aberrantly activated in tauopathies, causes impairment in ALP, leading to excess tau secretion. This effect, together with increased intracellular tau accumulation, contributes to enhanced spreading of tau. Our findings suggest that inhibition of p300/CBP as a novel approach to correct ALP dysfunction and block disease progression in tauopathy.

scholarly journals New Class of Anti-Inflammatory Therapeutics Based on Gold (III) Complexes in Intestinal Inflammation–Proof of Concept Based on In Vitro and In Vivo Studies

2021 ◽  
Vol 22 (6) ◽  
pp. 3121
Author(s):  
Julia B. Krajewska ◽  
Jakub Włodarczyk ◽  
Damian Jacenik ◽  
Radzisław Kordek ◽  
Przemysław Taciak ◽  
...  
Keyword(s):  
Mouse Model ◽  
Intestinal Inflammation ◽  
Therapeutic Potential ◽  
Gastrointestinal Diseases ◽  
Neutral Red ◽  
Water Soluble ◽  
In Vivo Studies ◽  
Anti Inflammatory

Inflammatory bowel diseases (IBD) are at the top of the worldwide rankings for gastrointestinal diseases as regards occurrence, yet efficient and side-effect-free treatments are currently unavailable. In the current study, we proposed a new concept for anti-inflammatory treatment based on gold (III) complexes. A new gold (III) complex TGS 121 was designed and screened in the in vitro studies using a mouse macrophage cell line, RAW264.7, and in vivo, in the dextran sulphate sodium (DSS)-induced mouse model of colitis. Physicochemical studies showed that TGS 121 was highly water-soluble; it was stable in water, blood, and lymph, and impervious to sunlight. In lipopolysaccharide (LPS)-stimulated RAW264.7 cells, the complex showed a potent anti-inflammatory profile, as evidenced in neutral red uptake and Griess tests. In the DSS-induced mouse model of colitis, the complex administered in two doses (1.68 μg/kg, intragastrically, and 16.8 μg/kg, intragastrically, once daily) produced a significant (* p < 0.05) anti-inflammatory effect, as shown by macroscopic score. The mechanism of action of TGS 121 was related to the enzymatic and non-enzymatic antioxidant system; moreover, TGS 121 induced changes in the tight junction complexes expression in the intestinal wall. This is the first study proving that gold (III) complexes may have therapeutic potential in the treatment of IBD.

scholarly journals Bystander Activation of Cytotoxic T Cells: Studies on the Mechanism and Evaluation of In Vivo Significance in a Transgenic Mouse Model

1997 ◽  
Vol 185 (7) ◽  
pp. 1241-1252 ◽  
Author(s):  
Stephan Ehl ◽  
Joachim Hombach ◽  
Peter Aichele ◽  
Hans Hengartner ◽  
Rolf M. Zinkernagel
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Vaccinia Virus ◽  
Transgenic Mouse ◽  
Rare Event ◽  
Transgenic Mouse Model ◽  
Bystander Activation

Bystander activation, i.e., activation of T cells specific for an antigen X during an immune response against antigen Y may occur during viral infections. However, the low frequency of bystander-activated T cells has rendered it difficult to define the mechanisms and possible in vivo relevance of this nonspecific activation. This study uses transgenic mice expressing a major histocompatibility complex class I–restricted TCR specific for glycoprotein peptide 33-41 of lymphocytic choriomeningitis virus (LCMV) to overcome this limitation. CD8+ T cells from specific pathogen-free maintained, unimmunized “naive” TCR transgenic mice can differentiate into LCMV-specific cytolytic effector CTL during infections with vaccinia virus or Listeria monocytogenes in vivo or mixed lymphocyte culture in vitro. We show that in these model situations (a) nonspecifically activated CTL are able to confer antiviral protection in vivo, (b) bystander activation is largely independent of the expression of a second T cell receptor of different specificity, (c) bystander activation is not mediated by a broadly cross-reactive TCR, but rather by cytokines, (d) bystander activation can be mediated by cytokines such as IL-2, but not α/β-IFN in vitro; (e) bystander activation is, overall, a rare event, occuring in vivo in roughly 1 in 200 of the LCMV-specific CTL during infection of TCR transgenic mice with vaccinia virus; (f) bystander activation does not have a significant functional impact on nontransgenic CTL memory under the conditions tested; and (g) even in the TCR transgenic situation, where unphysiologically high numbers of T cells of a single specificity are present, bystander activation is not sufficient to cause clinically manifest autoimmune disease in a transgenic mouse model of diabetes. We conclude that although bystander activation via cytokines may generate cytolytically active CTL from naive precursors, quantitative considerations suggest that this is usually not of major biological consequence.

PRT060318, a Novel Syk Inhibitor, Prevents Heparin-Induced Thrombocytopenia in a Transgenic Mouse Model

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 269-269 ◽  
Author(s):  
Michael P. Reilly ◽  
Uma Sinha ◽  
Pierrette Andre ◽  
Scott M. Taylor ◽  
Yvonne Pak ◽  
...  
Keyword(s):  
Body Weight ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Platelet Activation ◽  
Transgenic Mouse Model ◽  
Heparin Induced Thrombocytopenia ◽  
Syk Inhibitor ◽  
Induced Aggregation

Abstract Heparin-induced thrombocytopenia (HIT), in which patients develop antibodies to complexes formed by heparin and platelet factor 4 (PF4), is the most frequent drug-induced immune thrombocytopenia. Extensive studies in vitro and our previous studies in vivo using a transgenic mouse model of HIT have shown that antibodies reactive with heparin-PF4 complexes lead to FcgRIIa receptor-mediated platelet activation. In this study we investigated whether PRT060318 (PRT318), a novel Syk inhibitor, prevents HIT antibody-mediated platelet activation both in vitro and in vivo. PRT318 at concentrations of 0.3 to 3 μM completely inhibited HIT immune complex (IC)-induced aggregation in both human and transgenic mouse platelets. In the absence of the inhibitor, HIT IC-induced final aggregation was 50–60%. At concentrations of PRT318 less than 0.1 μM, or in the presence of vehicle only, there was no inhibition of aggregation. Aggregation was not inhibited by PRT318 at any concentration when platelets were stimulated by ADP (5–20 μM final concentration). We also show that PRT318 prevents HIT IC-induced thrombocytopenia in vivo using a transgenic mouse HIT model. All mice were treated with KKO, a mouse monoclonal HIT antibody. On days 1 to 4 following antibody injection, the experimental group (n = 13) received orally dosed PRT318 (30 mg/kg body weight) twice a day by gavage while the control group (n = 11) was similarly treated with vehicle only (water). Both experimental and control mice were injected with heparin (1600 U/kg body weight, SQ, once daily). Nadir platelet counts of PRT318-treated mice were significantly higher than control mice (89.8 ± 1.1% of baseline vs. 48.8 ± 6.7%; p = 0.00003). The PRT318 concentration, 2 hrs post dose, in mouse plasma from treated mice was measured as 7.1 μM, consistent with the concentration which blocked FcgRIIa-mediated platelet activation in vitro. These studies demonstrate that Syk inhibitor PRT318 is an active agent in HIT. Figure Figure

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