Transgenic expression of the HERV-W envelope protein leads to polarized glial cell populations and a neurodegenerative environment.

The human endogenous retrovirus type W (HERV-W) has been identified and repeatedly confirmed as human-specific pathogenic entity affecting many cell types in multiple sclerosis (MS). Our recent contributions revealed the encoded envelope (ENV) protein to disturb myelin repair by interfering with oligodendroglial precursor differentiation and by polarizing microglial cells toward an axon-damage phenotype. Indirect proof of ENV's antiregenerative and degenerative activities has been gathered recently in clinical trials using a neutralizing anti-ENV therapeutic antibody. Yet direct proof of its mode of action can only be presented here based on transgenic ENV expression in mice. Upon demyelination, we observed myelin repair deficits, neurotoxic microglia and astroglia, and increased axon degeneration. Experimental autoimmune encephalomyelitis activity progressed faster in mutant mice equally accompanied by activated glial cells. This study therefore provides direct evidence on HERV-W ENV's contribution to the overall negative impact of this activated viral entity in MS.

S1PR-1/5 modulator RP-101074 shows beneficial effects in a model of central nervous system degeneration.

Introduction: In multiple sclerosis (MS), chronic disability primarily stems from axonal and neuronal degeneration, a condition resistant to conventional immunosuppressive or immunomodulatory treatments. Recent research has indicated that selective sphingosine-1-phosphate receptor S1PR-1 and -5 modulators yield positive effects in progressive MS and mechanistic models of inflammation-driven neurodegeneration and demyelination. Methods: In this study, the S1PR-1/-5 modulator RP-101074 was evaluated as a surrogate for ozanimod in the non-inflammatory, primary degenerative animal model of light-induced photoreceptor loss (LI-PRL) in CX3CR1-GFP mice to assess potential neuroprotective effects, independent of its immunomodulatory mechanism of action. Results: Prophylactic administration of RP-101074 demonstrated protective effects in the preclinical, non-inflammatory LI-PRL animal model, following a bell-shaped dose-response curve. RP-101074 treatment also revealed activity-modulating effects on myeloid cells, specifically, CX3CR1+ cells, significantly reducing the marked infiltration occurring one week post-irradiation. Treatment with RP-101074 produced beneficial outcomes on both retinal layer thickness and visual function as evidenced by optical coherence tomography (OCT) and optomotor response (OMR) measurements, respectively. Additionally, the myelination status and the quantity of neural stem cells in the optic nerve suggest that RP-101074 may play a role in the activation and/or recruitment of neural stem cells and oligodendrocyte progenitor cells, respectively. Conclusion/Discussion: The data from our study suggest that RP-101074 may have a broader role in MS treatment beyond immunomodulation, potentially offering a novel approach to mitigate neurodegeneration, a core contributor to chronic disability in MS.

Semi-Automated Live Tracking of Microglial Activation in CX3CR1GFP Mice During Experimental Autoimmune Encephalomyelitis by Confocal Scanning Laser Ophthalmoscopy.

Confocal scanning laser ophthalmoscopy (cSLO) is a non-invasive technique for real-time imaging of the retina. We developed a step-by-step protocol for the semi-automatic evaluation of myeloid cells in cSLO images from CX3CR1GFP mice, expressing green fluorescent protein (GFP) under control of the endogenous CX3C chemokine receptor 1 locus. We identified cSLO parameters allowing us to distinguish animals with experimental autoimmune encephalomyelitis (EAE) from sham-treated/naïve animals. Especially cell count (CC) and the total microglial area (SuA) turned out to be reliable parameters. Comparing the cSLO results with clinical parameters, we found significant correlations between the clinical EAE score and the SuA and of the inner retinal layer thickness, measured by optical coherence tomography, with the CC as well as the SuA. As a final step, we performed immunohistochemistry to confirm that the GFP-expressing cells visualized by the cSLO are Iba1 positive and validated the step-by-step protocol against manual counting. We present a semi-automatic step-by-step protocol with a balance between fast data evaluation and adequate accuracy, which is optimized by the option to manually adapt the contrast threshold. This protocol may be useful for numerous research questions on the role of microglial polarization in models of inflammatory and degenerating CNS diseases involving the retina.

Nano-sulforaphane attenuates PhIP-induced early abnormal embryonic neuro-development.

BACKGROUND: 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyrimidine (PhIP), one of the most abundant heterocyclic aromatic amines (HAA) formed by cooking meat at high temperatures, may modify humans and rodents through the metabolic process prior to affecting nervous system development. In humans and rodents may be modified by metabolic processes and then affecting nervous system development. METHODS: In this paper, PhIP was used to prepare a chicken embryo model with abnormal embryonic nervous system defects. Sulforaphane (SFN) is a derivative of a glucosinolate, which is abundant in cruciferous vegetables, and can pass through the placental barrier. Moreover, SFN has antioxidant and anti-apoptotic functions and is considered as a bioactive antioxidant with significant neuroprotective effects. Nano-sulforaphane (Nano-SFN, sulforaphane nanoparticles) was prepared by self-assembly using biocompatible, biodegradable methoxy polyethylene glycol 5000-b-polyglutamic acid 10,000 (mPEG5K-PGA10K) as the substrate, to explore the new application of Nano-SFN and its modified compounds as leading compounds in protecting against the abnormal development of the embryonic nervous system. RESULTS: The results show that Nano-SFN could protect against PhIP-induced central nervous system (CNS, derived from neural tube) and peripheral nervous system (PNS, derived from neural crest cells, NCCs) defects and neural tube defects (NTDs), and increase the embryo survival rate. CONCLUSIONS: This study indicates that Nano-SFN can effectively alleviate the developmental defects of embryonic nervous system induced by PhIP in the microenvironment and has a protective effect on embryonic development. It not only helps with expanding the application of SFN and improving its medicinal value, but also provides a possibility of SFN being developed as a novel drug for neuroprotection.