Nogo-A neutralization in the central nervous system with a blood-brain barrier-penetrating antibody.

The poor penetration of monoclonal antibodies (mAb) across the blood-brain barrier (BBB) impedes the development of regenerative therapies for neurological diseases. For example, Nogo-A is a myelin-associated protein highly expressed in the central nervous system (CNS) whose inhibitory effects on neuronal plasticity can be neutralized with direct administration of 11C7 mAb in CNS tissues/fluids, but not with peripheral administrations such as intravenous injections. Therefore, in the present study, we engineered a CNS-penetrating antibody against Nogo-A by combining 11C7 mAb and the single-chain variable fragment (scFv) of 8D3, a rat antibody binding transferrin receptor 1 (TfR) and mediating BBB transcytosis (11C7-scFv8D3).

Predicting glucocorticoid resistance in multiple sclerosis relapse via a whole blood transcriptomic analysis.

Aims: Treatment of multiple sclerosis (MS) relapses consists of short-term administration of high-dose glucocorticoids (GCs). However, over 40% of patients show an insufficient response to GC treatment. We aimed to develop a predictive model for such GC resistance.

Nogo-A antibody delivery through the olfactory mucosa mitigates experimental autoimmune encephalomyelitis in the mouse CNS.

Systemic administration of Nogo-A-neutralizing antibody ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, the blood-brain barrier (BBB) is a major obstacle limiting the passage of systemically applied antibody to the CNS. To bypass the BBB, in the present study we tested the intranasal route of administration by targeting the olfactory mucosa with the Nogo-A-blocking antibody 11C7 mAb in myelin oligodendrocyte glycoprotein-induced EAE.

B cell-dependent EAE induces visual deficits in the mouse with similarities to human autoimmune demyelinating diseases.

Background: In the field of autoimmune demyelinating diseases, visual impairments have extensively been studied using the experimental autoimmune encephalomyelitis (EAE) mouse model, which is classically induced by immunization with myelin oligodendrocyte glycoprotein peptide (MOG). However, this model does not involve B cells like its human analogs. New antigens have thus been developed to induce a B cell-dependent form of EAE that better mimics human diseases.

The Lack of Amyloidogenic Activity Is Persistent in Old WT and APP/PS1ΔE9 Mouse Retinae.

We have previously reported that vision decline was not associated with amyloidogenesis processing in aging C57BL/6J wild-type (WT) mice and in a mouse model of Alzheimer's disease, the APP/PS1ΔE9 transgenic mouse model (APP/PS1). This conclusion was drawn using middle-aged (10-13 months old) mice. Here, we hypothesized that compared with hippocampal and cortical neurons, the weak amyloidogenic activity of retinal neurons may result in a detectable release of amyloid β (Aβ) only in aged mice, i.

Tau modulates visual plasticity in adult and old mice.

Tau is a microtubule-associated protein involved in Alzheimer's disease. However, little is known on its physiological function in the healthy central nervous system. Here, we observed that the expression of Tau isoforms was modulated by neuronal maturation and visual experience in the mouse retina and in the visual cortex.

Tau Gene Deletion does not Influence Axonal Regeneration and Retinal Neuron Survival in the Injured Mouse Visual System.

In the present study, we hypothesized that the microtubule-associated protein Tau may influence retinal neuron survival and axonal regeneration after optic nerve injury. To test this hypothesis, the density of retinal ganglion cells was evaluated by immunostaining retinal flat-mounts for RNA-binding protein with multiple splicing (RBPMS) two weeks after optic nerve micro-crush lesion in Tau-deprived (Tau knock-out (KO)) and wild-type (WT) mice. Axon growth was determined on longitudinal sections of optic nerves after anterograde tracing.

Nogo-A-targeting antibody promotes visual recovery and inhibits neuroinflammation after retinal injury.

N-Methyl-D-aspartate (NMDA)-induced neuronal cell death is involved in a large spectrum of diseases affecting the brain and the retina such as Alzheimer's disease and diabetic retinopathy. Associated neurological impairments may result from the inhibition of neuronal plasticity by Nogo-A. The objective of the current study was to determine the contribution of Nogo-A to NMDA excitotoxicity in the mouse retina.

Corrigendum: Human Tau Expression Does Not Induce Mouse Retina Neurodegeneration, Suggesting Differential Toxicity of Tau in Brain vs. Retinal Neurons.

[This corrects the article DOI: 10.3389/fnmol.2018.

Human Tau Expression Does Not Induce Mouse Retina Neurodegeneration, Suggesting Differential Toxicity of Tau in Brain vs. Retinal Neurons.

The implication of the microtubule-associated protein (MAP) Tau in the ocular manifestations of Alzheimer's disease (AD) is elusive due to the lack of relevant animal model. However, signs of AD have been reported in the brain of transgenic mice expressing human Tau (hTau). To assess whether hTau is sufficient to induce AD pathogenesis in the retina as well, in the present study, we compared the retinal structure and function of KO mice deprived of Tau (mTKO) with those of transgenic mice expressing hTau.

Nogo-A inhibits vascular regeneration in ischemic retinopathy.

Nogo-A is a potent glial-derived inhibitor of axon growth in the injured CNS and acts as a negative regulator of developmental angiogenesis by inhibiting vascular endothelial cell migration. However, its function in pathological angiogenesis has never been studied after ischemic injury in the CNS. Using the mouse model of oxygen-induced retinopathy (OIR) which yields defined zones of retinal ischemia, our goal was to investigate the role of Nogo-A in vascular regeneration.

Sphingosine 1-Phosphate Receptor 1 Modulates CNTF-Induced Axonal Growth and Neuroprotection in the Mouse Visual System.

The lack of axonal regeneration and neuronal cell death causes permanent neurological deficits in the injured CNS. Using the classical CNS injury model of optic nerve crush in mice, (CNTF) was found to stimulate retinal ganglion cell (RGC) survival and axonal growth, but in an incomplete fashion. The elucidation of molecular mechanisms impairing CNTF-induced axonal regeneration is paramount to promote visual recovery.

Nonamyloidogenic processing of amyloid beta precursor protein is associated with retinal function improvement in aging male APP/PS1ΔE9 mice.

Vision declines during normal aging and in Alzheimer's disease (AD). Although the toxic role of amyloid beta (Aβ) has been established in AD pathogenesis, its influence on the aging retina is unclear. Using APP/PS1ΔE9 transgenic (TG) mice, a classical AD model, the retinal cell function and survival was assessed by electroretinogram (ERG) recordings and immunofluorescent stainings.

Sphingosine 1-phosphate receptor 1 is required for retinal ganglion cell survival after optic nerve trauma.

In this study, we used a classical optic nerve injury model to address the function of the sphingosine 1-phosphate (S1P)-S1P receptor (S1PR) axis in retinal ganglion cell (RGC) death and axonal growth. After lesion, the expression of S1PR1 was generally reduced in axotomized RGCs but persisted in αRGCs, a subpopulation of injury-resistant RGCs. Silencing S1PR1 with an adeno-associated virus serotype 2 (AAV2) containing a shRNA specific to S1PR1 (AAV2.

Reticulon 4A/Nogo-A influences the distribution of Kir4.1 but is not essential for potassium conductance in retinal Müller glia.

In the adult retina, we have previously shown that Nogo-A was highly expressed in Müller glia. However, the role of Nogo-A in the glial cell physiology is not clear. In this study, we investigated the possible influence that Nogo-A may exert on other polarized molecules in Müller cells, in particular inwardly rectifying potassium channel 4.

Nogo-A deletion increases the plasticity of the optokinetic response and changes retinal projection organization in the adult mouse visual system.

The inhibitory action of Nogo-A on axonal growth has been well described. However, much less is known about the effects that Nogo-A could exert on the plasticity of neuronal circuits under physiological conditions. We investigated the effects of Nogo-A knock-out (KO) on visual function of adult mice using the optokinetic response (OKR) and the monocular deprivation (MD)-induced OKR plasticity and analyzed the anatomical organization of the eye-specific retinal projections.

The Ephrin receptor EphA4 restricts axonal sprouting and enhances branching in the injured mouse optic nerve.

The lack of axonal regeneration in the adult central nervous system is in part attributable to the presence of inhibitory molecules present in the environment of injured axons such as the myelin-associated proteins Nogo-A and MAG and the repulsive guidance molecules Ephrins, Netrins and Semaphorins. In the present study, we hypothesized that EphA4 and one of its potential binding partners EphrinA3 may participate in the inhibition of adult axon regeneration in the model of adult mouse optic nerve injury. Axonal regeneration was analysed in three dimensions after tissue clearing of EphA4 knockout (KO), EphrinA3 KO and wild-type (WT) optic nerves.

New mouse retinal stroke model reveals direction-selective circuit damage linked to permanent optokinetic response loss.

Purpose: Ischemic insults give rise to severe visual deficits after blood vessel occlusion. In this study we investigated the effects of retinal stroke on the direction-selective circuit of the inner retina in a new adult mouse model.

Methods: The inner retinal blood flow was interrupted for 60 minutes by ligating the ophthalmic arteries and veins in the optic nerve sheath.

Targeting the bHLH transcriptional networks by mutated E proteins in experimental glioma.

Glioblastomas (GB) are aggressive primary brain tumors. Helix-loop-helix (HLH, ID proteins) and basic HLH (bHLH, e.g.

Long-distance axonal regeneration induced by CNTF gene transfer is impaired by axonal misguidance in the injured adult optic nerve.

The optic nerve crush injury is a well-accepted model to study the mechanisms of axonal regeneration after trauma in the CNS. The infection of retinal ganglion cells (RGCs) with an adeno-associated virus serotype 2 - ciliary neurotrophic factor (AAV2.CNTF) was previously shown to stimulate axonal regeneration.

Longitudinal assessment of retinal structure and function reveals a rod-cone degeneration in a guinea pig model initially presented as night blind.

We have previously reported a naturally occurring retinopathy in a population of guinea pigs, where the affected animals presented a defect of the rod-mediated vision. The purpose of this study was to investigate if the mutants were affected with a stationary or degenerative retinopathy and to identify the cellular origin of this unique disorder. Electroretinogram (ERG) [postnatal day 1 (P1) to P450], light (LM) and electron microscopy (EM) [P5, P150, P450], and immunohistochemistry [P30, P150, P450] were evaluated from normal and mutant animals.

Pax6-positive Müller glia cells express cell cycle markers but do not proliferate after photoreceptor injury in the mouse retina.

In lower vertebrates, such as fish, Müller glia plays an essential role in the restoration of visual function after retinal degeneration by transdifferentiating into photoreceptors and other retinal neurons. During this process, Müller cells re-enter the cell cycle, proliferate, and migrate from the inner nuclear layer (INL) to the photoreceptor layer where they express photoreceptor-specific markers. This process of Müller cell transdifferentiation is absent in mammals, and the loss of photoreceptors leads to permanent vision deficits.

HIF1A is essential for the development of the intermediate plexus of the retinal vasculature.

Purpose: HIF1A is one of the major transcription factors that regulate tissue response to low oxygen tension. It controls expression of a large number of genes involved in cell survival, proliferation, angiogenesis, and other cellular processes. HIF1A is present at increased levels in the early postnatal retina.