The complex relationship between obesity and neurodegenerative diseases: an updated review.

Obesity is a global epidemic, affecting roughly 30% of the world's population and predicted to rise. This disease results from genetic, behavioral, societal, and environmental factors, leading to excessive fat accumulation, due to insufficient energy expenditure. The adipose tissue, once seen as a simple storage depot, is now recognized as a complex organ with various functions, including hormone regulation and modulation of metabolism, inflammation, and homeostasis. Obesity is associated with a low-grade inflammatory state and has been linked to neurodegenerative diseases like multiple sclerosis (MS), Alzheimer's (AD), and Parkinson's (PD). Mechanistically, reduced adipose expandability leads to hypertrophic adipocytes, triggering inflammation, insulin and leptin resistance, blood-brain barrier disruption, altered brain metabolism, neuronal inflammation, brain atrophy, and cognitive decline. Obesity impacts neurodegenerative disorders through shared underlying mechanisms, underscoring its potential as a modifiable risk factor for these diseases. Nevertheless, further research is needed to fully grasp the intricate connections between obesity and neurodegeneration. Collaborative efforts in this field hold promise for innovative strategies to address this complex relationship and develop effective prevention and treatment methods, which also includes specific diets and physical activities, ultimately improving quality of life and health.

Women in the field of multiple sclerosis: How they contributed to paradigm shifts.

History is full of women who made enormous contributions to science. While there is little to no imbalance at the early career stage, a decreasing proportion of women is found as seniority increases. In the multiple sclerosis (MS) field, 44% of first authors and only 35% of senior authors were female. So, in this review, we highlight ground-breaking research done by women in the field of MS, focusing mostly on their work as principal investigators. MS is an autoimmune disorder of the central nervous system (CNS), with evident paradigm shifts in the understating of its pathophysiology. It is known that the immune system becomes overactivated and attacks myelin sheath surrounding axons. The resulting demyelination disrupts the communication signals to and from the CNS, which causes unpredictable symptoms, depending on the neurons that are affected. Classically, MS was reported to cause mostly physical and motor disabilities. However, it is now recognized that cognitive impairment affects more than 50% of the MS patients. Another shifting paradigm was the involvement of gray matter in MS pathology, formerly considered to be a white matter disease. Additionally, the identification of different T cell immune subsets and the mechanisms underlying the involvement of B cells and peripheral macrophages provided a better understanding of the immunopathophysiological processes present in MS. Relevantly, the gut-brain axis, recognized as a bi-directional communication system between the CNS and the gut, was found to be crucial in MS. Indeed, gut microbiota influences not only different susceptibilities to MS pathology, but it can also be modulated in order to positively act in MS course. Also, after the identification of the first microRNA in 1993, the role of microRNAs has been investigated in MS, either as potential biomarkers or therapeutic agents. Finally, concerning MS therapeutical approaches, remyelination-based studies have arisen on the spotlight aiming to repair myelin loss/neuronal connectivity. Altogether, here we emphasize the new insights of remarkable women that have voiced the impact of cognitive impairment, white and gray matter pathology, immune response, and that of the CNS-peripheral interplay on MS diagnosis, progression, and/or therapy efficacy, leading to huge breakthroughs in the MS field.

Emerging Role of miR-21-5p in Neuron-Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with neuron-glia dysfunction and dysregulated miRNAs. We previously reported upregulated miR-124/miR-21 in AD neurons and their exosomes. However, their glial distribution, phenotypic alterations and exosomal spread are scarcely documented. Here, we show glial cell activation and miR-21 overexpression in mouse organotypic hippocampal slices transplanted with SH-SY5Y cells expressing the human APP695 Swedish mutation. The upregulation of miR-21 only in the CSF from a small series of mild cognitive impairment (MCI) AD patients, but not in non-AD MCI individuals, supports its discriminatory potential. Microglia, neurons, and astrocytes differentiated from the same induced pluripotent stem cells from PSEN1ΔE9 AD patients all showed miR-21 elevation. In AD neurons, miR-124/miR-21 overexpression was recapitulated in their exosomes. In AD microglia, the upregulation of iNOS and miR-21/miR-146a supports their activation. AD astrocytes manifested a restrained inflammatory profile, with high miR-21 but low miR-155 and depleted exosomal miRNAs. Their immunostimulation with C1q + IL-1α + TNF-α induced morphological alterations and increased S100B, inflammatory transcripts, sAPPß, cytokine release and exosomal miR-21. PPARα, a target of miR-21, was found to be repressed in all models, except in neurons, likely due to concomitant miR-125b elevation. The data from these AD models highlight miR-21 as a promising biomarker and a disease-modifying target to be further explored.

Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment.

BACKGROUND: Inhibiting programmed cell death protein 1 (PD-1) or PD-ligand 1 (PD-L1) has shown exciting clinical outcomes in diverse human cancers. So far, only monoclonal antibodies are approved as PD-1/PD-L1 inhibitors. While significant clinical outcomes are observed on patients who respond to these therapeutics, a large proportion of the patients do not benefit from the currently available immune checkpoint inhibitors, which strongly emphasize the importance of developing new immunotherapeutic agents. METHODS: In this study, we followed a transdisciplinary approach to discover novel small molecules that can modulate PD-1/PD-L1 interaction. To that end, we employed in silico analyses combined with in vitro, ex vivo, and in vivo experimental studies to assess the ability of novel compounds to modulate PD-1/PD-L1 interaction and enhance T-cell function. RESULTS: Accordingly, in this study we report the identification of novel small molecules, which like anti-PD-L1/PD-1 antibodies, can stimulate human adaptive immune responses. Unlike these biological compounds, our newly-identified small molecules enabled an extensive infiltration of T lymphocytes into three-dimensional solid tumor models, and the recruitment of cytotoxic T lymphocytes to the tumor microenvironment in vivo, unveiling a unique potential to transform cancer immunotherapy. CONCLUSIONS: We identified a new promising family of small-molecule candidates that regulate the PD-L1/PD-1 signaling pathway, promoting an extensive infiltration of effector CD8 T cells to the tumor microenvironment.

S100B inhibition protects from chronic experimental autoimmune encephalomyelitis.

Studies have correlated excessive S100B, a small inflammatory molecule, with demyelination and associated inflammatory processes occurring in multiple sclerosis. The relevance of S100B in multiple sclerosis pathology brought an emerging curiosity highlighting its use as a potential therapeutic target to reduce damage during the multiple sclerosis course, namely during inflammatory relapses. We examined the relevance of S100B and further investigated the potential of S100B-neutralizing small-molecule pentamidine in chronic experimental autoimmune encephalomyelitis. S100B depletion had beneficial pathological outcomes and based on promising results of a variety of S100B blockade strategies in an ex vivo demyelinating model, we choose pentamidine to assay its role in the in vivo experimental autoimmune encephalomyelitis. We report that pentamidine prevents more aggressive clinical symptoms and improves recovery of chronic experimental autoimmune encephalomyelitis. Blockade of S100B by pentamidine protects against oligodendrogenesis impairment and neuroinflammation by reducing astrocyte reactivity and microglia pro-inflammatory phenotype. Pentamidine also increased regulatory T cell density in the spinal cord suggesting an additional immunomodulatory action. These results showed the relevance of S100B as a main driver of neuroinflammation in experimental autoimmune encephalomyelitis and identified an uncharacterized mode of action of pentamidine, strengthening the possibility to use this drug as an anti-inflammatory and remyelinating therapy for progressive multiple sclerosis.

Protective Signature of IFNγ-Stimulated Microglia Relies on miR-124-3p Regulation From the Secretome Released by Mutant APP Swedish Neuronal Cells.

Microglia-associated inflammation and miRNA dysregulation are key players in Alzheimer's disease (AD) pathophysiology. Previously, we showed miR-124 upregulation in APP Swedish SH-SY5Y (SWE) and PSEN1 iPSC-derived neurons and its propagation by the secretome (soluble and exosomal fractions). After modulation with miR-124 mimic/inhibitor, we identified common responsive mechanisms between such models. We also reported miR-124 colocalization with microglia in AD patient hippocampi. Herein, we determined how miR-124 modulation in SWE cells influences microglia polarized subtypes in the context of inflammation. We used a coculture system without cell-to-cell contact formed by miR-124 modulated SWE cells and human CHME3 microglia stimulated with interferon-gamma (IFNγ-MG), in which we assessed their adopted gene/miRNA profile and proteomic signature. The increase of miR-124 in SWE cells/secretome (soluble and exosomal) was mimicked in IFNγ-MG. Treatment of SWE cells with the miR-124 inhibitor led to RAGE overexpression and loss of neuronal viability, while the mimic caused RAGE/HMGB1 downregulation and prevented mitochondria membrane potential loss. When accessing the paracrine effects on microglia, SWE miR-124 inhibitor favored their IFNγ-induced inflammatory signature (upregulated RAGE/HMGB1/iNOS/IL-1ß; downregulated IL-10/ARG-1), while the mimic reduced microglia activation (downregulated TNF-α/iNOS) and deactivated extracellular MMP-2/MMP-9 levels. Microglia proteomics identified 113 responsive proteins to SWE miR-124 levels, including a subgroup of 17 proteins involved in immune function/inflammation and/or miR-124 targets. A total of 72 proteins were downregulated (e.g., MAP2K6) and 21 upregulated (e.g., PAWR) by the mimic, while the inhibitor also upregulated 21 proteins and downregulated 17 (e.g., TGFB1, PAWR, and EFEMP1). Other targets were associated with neurodevelopmental mechanisms, synaptic function, and vesicular trafficking. To examine the source of miR-124 variations in microglia, we silenced the RNase III endonuclease Dicer1 to block miRNA canonical biogenesis. Despite this suppression, the coculture with SWE cells/exosomes still raised microglial miR-124 levels, evidencing miR-124 transfer from neurons to microglia. This study is pioneer in elucidating that neuronal miR-124 reshapes microglia plasticity and in revealing the relevance of neuronal survival in mechanisms underlying inflammation in AD-associated neurodegeneration. These novel insights pave the way for the application of miRNA-based neuropharmacological strategies in AD whenever miRNA dysregulated levels are identified during patient stratification.

Differences in Immune-Related Genes Underlie Temporal and Regional Pathological Progression in 3xTg-AD Mice.

The prevalence of Alzheimer's disease (AD), the most common cause of age-associated dementia, is estimated to increase over the next decades. Evidence suggests neuro-immune signaling deregulation and risk genes beyond the amyloid-ß (Aß) deposition in AD pathology. We examined the temporal profile of inflammatory mediators and microglia deactivation/activation in the brain cortex and hippocampus of 3xTg-AD mice at 3- and 9-month-old. We found upregulated APP processing, decreased expression of CD11b, CX3CR1, MFG-E8, TNF-α, IL-1ß, MHC-II and C/EBP-α and increased miR-146a in both brain regions in 3-month-old 3xTG-AD mice, suggestive of a restrictive regulation. Enhanced TNF-α, IL-1ß, IL-6, iNOS, SOCS1 and Arginase 1 were only present in the hippocampus of 9-month-old animals, though elevation of HMGB1 and reduction of miR-146a and miR-124 were common features in the hippocampus and cortex regions. miR-155 increased early in the cortex and later in both regions, supporting its potential as a biomarker. Candidate downregulated target genes by cortical miR-155 included Foxo3, Runx2 and CEBPß at 3 months and Foxo3, Runx2 and Socs1 at 9 months, which are implicated in cell survival, but also in Aß pathology and microglia/astrocyte dysfunction. Data provide new insights across AD state trajectory, with divergent microglia phenotypes and inflammatory-associated features, and identify critical targets for drug discovery and combinatorial therapies.

Improved Assessment of Overall Health in Variably Aged Murine Models of Multiple Sclerosis With a Novel Frailty Index Tool.

The experimental autoimmune encephalomyelitis (EAE) model is the most commonly used animal model of multiple sclerosis (MS). However, phenotypic characterization of mice based on the traditional 5-point clinical paralysis scale does not fully capture disease progression. The frailty index (FI) conceptualizes frailty as the accumulation of health deficits and it is widely used to assess overall health in aging humans and preclinical models. Here, we adapted an established mouse FI tool for use in EAE mice and determined whether this could evaluate general signs of health in variably aged female EAE mice. The EAE-Clinical FI included 34 items related to clinical signs and deficits characteristic of aging and MS. This tool clearly showed more detailed EAE progression and severity at all ages, highlighting changes in systems other than motor paralysis measured with the traditional 5-point paralysis scale. When we induced disease at 3 and 6 months of age, mice showed typical EAE clinical manifestations with peak disease severity between 17 and 19 days post-induction and mean frailty scores of 0.36 ± 0.04 (3-month-old) and 0.43 ± 0.05 (6-month-old). By contrast, disease severity peaked after 14 days in 12-month-old mice. They showed atypical signs including wobbling, early belly drag, and splayed hindlegs that were better captured with the EAE-Clinical FI. Peak frailty scores also were higher than those of younger animals (0.54 ± 0.04). As MS most often develops in young to middle-aged people, this new tool may have significant value for use in EAE animal studies as a first step toward translation to people with MS.

BASHY Dye Platform Enables the Fluorescence Bioimaging of Myelin Debris Phagocytosis by Microglia during Demyelination.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that is characterized by the presence of demyelinated regions with accumulated myelin lipid debris. Importantly, to allow effective remyelination, such debris must be cleared by microglia. Therefore, the study of microglial activity with sensitive tools is of great interest to better monitor the MS clinical course. Using a boronic acid-based (BASHY) fluorophore, specific for nonpolar lipid aggregates, we aimed to address BASHY's ability to label nonpolar myelin debris and image myelin clearance in the context of demyelination. Demyelinated ex vivo organotypic cultures (OCSCs) and primary microglia cells were immunostained to evaluate BASHY's co-localization with myelin debris and also to evaluate BASHY's specificity for phagocytosing cells. Additionally, mice induced with experimental autoimmune encephalomyelitis (EAE) were injected with BASHY and posteriorly analyzed to evaluate BASHY+ microglia within demyelinated lesions. Indeed, in our in vitro and ex vivo studies, we showed a significant increase in BASHY labeling in demyelinated OCSCs, mostly co-localized with Iba1-expressing amoeboid/phagocytic microglia. Most importantly, BASHY's presence was also found within demyelinated areas of EAE mice, essentially co-localizing with lesion-associated Iba1+ cells, evidencing BASHY's potential for the in vivo bioimaging of myelin clearance and myelin-carrying microglia in regions of active demyelination.

Neuronal Dynamics and miRNA Signaling Differ between SH-SY5Y APPSwe and PSEN1 Mutant iPSC-Derived AD Models upon Modulation with miR-124 Mimic and Inhibitor.

Neuronal miRNA dysregulation may have a role in the pathophysiology of Alzheimer's disease (AD). miRNA(miR)-124 is largely abundant and a critical player in many neuronal functions. However, the lack of models reliably recapitulating AD pathophysiology hampers our understanding of miR-124's role in the disease. Using the classical human SH-SY5Y-APP695 Swedish neuroblastoma cells (SH-SWE) and the PSEN1 mutant iPSC-derived neurons (iNEU-PSEN), we observed a sustained upregulation of miR-124/miR-125b/miR-21, but only miR-124 was consistently shuttled into their exosomes. The miR-124 mimic reduced APP gene expression in both AD models. While miR-124 mimic in SH-SWE neurons led to neurite outgrowth, mitochondria activation and small Aß oligomer reduction, in iNEU-PSEN cells it diminished Tau phosphorylation, whereas miR-124 inhibitor decreased dendritic spine density. In exosomes, cellular transfection with the mimic predominantly downregulated miR-125b/miR-21/miR-146a/miR-155. The miR-124 inhibitor upregulated miR-146a in the two experimental cell models, while it led to distinct miRNA signatures in cells and exosomes. In sum, though miR-124 function may be dependent on the neuronal AD model, data indicate that keeping miR-124 level strictly controlled is crucial for proper neuronal function. Moreover, the iNEU-PSEN cellular model stands out as a useful tool for AD mechanistic studies and perhaps for the development of personalized therapeutic strategies.

Extracellular Vesicles in Blood: Sources, Effects, and Applications.

Extracellular vesicles (EVs) are important players for intercellular communication. EVs are secreted by almost all cell types; they can transfer information between nearby or distant cells, and they are highly abundant in body fluids. In this review, we describe the general characteristics of EVs, as well as isolation and characterization approaches. Then, we focus on one of the most relevant sources of EVs: the blood. Indeed, apart from EVs secreted by blood cells, EVs of diverse origins travel in the bloodstream. We present the numerous types of EVs that have been found in circulation. Besides, the implications of blood-derived EVs in both physiological and pathological processes are summarized, highlighting their potential as biomarkers for the diagnosis, treatment monitoring, and prognosis of several diseases, and also as indicators of physiological modifications. Finally, the applications of EVs introduced in the circulatory system are discussed. We describe the use of EVs from distinct origins, naturally produced or engineered, autologous, allogeneic, or even from different species and the effects they have when introduced in circulation. Therefore, the present work provides a comprehensive overview of the components, effects, and applications of EVs in blood.

Neuronal and glial CSF biomarkers in multiple sclerosis: a systematic review and meta-analysis.

Multiple sclerosis (MS) is a neurodegenerative disease associated with inflammatory demyelination and astroglial activation, with neuronal and axonal damage as the leading factors of disability. We aimed to perform a meta-analysis to determine changes in CSF levels of neuronal and glial biomarkers, including neurofilament light chain (NFL), total tau (t-tau), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein (GFAP), and S100B in various groups of MS (MS versus controls, clinically isolated syndrome (CIS) versus controls, CIS versus MS, relapsing-remitting MS (RRMS) versus progressive MS (PMS), and MS in relapse versus remission. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, we included 64 articles in the meta-analysis, including 4071 subjects. For investigation of sources of heterogeneity, subgroup analysis, meta-regression, and sensitivity analysis were conducted. Meta-analyses were performed for comparisons including at least three individual datasets. NFL, GFAP, t-tau, CHI3L1, and S100B were higher in MS and NFL, t-tau, and CHI3L1 were also elevated in CIS patients than controls. CHI3L1 was the only marker with higher levels in MS than CIS. GFAP levels were higher in PMS versus RRMS, and NFL, t-tau, and CHI3L1 did not differ between different subtypes. Only levels of NFL were higher in patients in relapse than remission. Meta-regression showed influence of sex and disease severity on NFL and t-tau levels, respectively and disease duration on both. Added to the role of these biomarkers in determining prognosis and treatment response, to conclude, they may serve in diagnosis of MS and distinguishing different subtypes.

Efficient Amino-Sulfhydryl Stapling on Peptides and Proteins Using Bifunctional NHS-Activated Acrylamides.

Widely used reagents in the peptide functionalization toolbox, Michael acceptors and N-hydroxysuccinimide (NHS) activated esters, are combined in NHS-activated acrylamides for efficient chemoselective amino-sulfhydryl stapling on native peptides and proteins. NHS-activated acrylamides allow for a fast functionalization of N-terminal cysteines (k2 =1.54±0.18×103  M-1 s-1 ) under dilute aqueous conditions, enabling selectivity over other nucleophilic amino acids. Additionally, the versatility of these new bioconjugation handles was demonstrated in the cross-linking of in-chain or C-terminal cysteines with nearby lysine residues. NHS-activated acrylamides are compatible with the use of other cysteine selective reagents, allowing for orthogonal dual-modifications. This strategy was successfully applied to the late-stage functionalization of peptides and proteins with a PEG unit, fluorescent probe, and cytotoxic agent. The level of molecular control offered by NHS-activated acrylamides is expected to promote amino-sulfhydryl stapling technology as a powerful strategy to design functional bioconjugates.

Designer Cathinones N-Ethylhexedrone and Buphedrone Show Different In Vitro Neurotoxicity and Mice Behaviour Impairment.

N-Ethylhexedrone (NEH) and buphedrone (Buph) are emerging synthetic cathinones (SC) with limited information about their detrimental effects within central nervous system. Objectives: To distinguish mice behavioural changes by NEH and Buph and validate their differential harmful impact on human neurons and microglia. In vivo safety data showed the typical induced behaviour of excitation and stereotypies with 4-64 mg/kg, described for other SC. Buph additionally produced jumping and aggressiveness signs, while NEH caused retropulsion and circling. Transient reduction in body-weight gain was obtained with NEH at 16 mg/kg and induced anxiolytic-like behaviour mainly with Buph. Both drugs generated place preference shift in mice at 4 and 16 mg/kg, suggestive of abuse potential. In addition, mice withdrawn NEH displayed behaviour suggestive of depression, not seen with Buph. When tested at 50-400 µM in human nerve cell lines, NEH and Buph caused neuronal viability loss at 100 µM, but only NEH produced similar results in microglia, indicating different cell susceptibilities. NEH mainly induced microglial late apoptosis/necrosis, while Buph caused early apoptosis. NEH was unique in triggering microglia shorter/thicker branches indicative of cell activation, and more effective in increasing microglial lysosomal biogenesis (100 µM vs. 400 µM Buph), though both produced the same effect on neurons at 400 µM. These findings indicate that NEH and Buph exert neuro-microglia toxicities by distinct mechanisms and highlight NEH as a specific inducer of microglia activation. Buph and NEH showed in vivo/in vitro neurotoxicities but enhanced specific NEH-induced behavioural and neuro-microglia dysfunctionalities pose safety concerns over that of Buph.

Linking Cognitive Impairment to Neuroinflammation in Multiple Sclerosis using neuroimaging tools.

Multiple sclerosis (MS) is a complex chronic immune disease in the central nervous system, causing neurological disability among young and middle-aged adults. Impaired cognition is now emerging as a major clinical symptom being present in more than 50% of MS patients. Recent data support that neuroinflammation mediated by glial cells plays a key part in MS course and, particularly, microglia is responsible for the pruning of synapses possibly impacting on vital neural networks maintenance. However, the knowledge of microglia-mediated mechanisms underlying cognitive impairment in MS is poor and unfortunately, there are no medicines to overcome this "invisible" symptom. Interestingly, the use of powerful diagnostic imaging tools as structural and functional MRI as well as PET brought new insights into some biological mechanisms, but no link between the possibility to use early visible alterations to predict cognitive deficits was clarified yet. In this review, we focus on the interplay between MS-related cognitive structures and neuroinflammation, specifically the presence of microglia and their reactivity. Moreover, we also discuss new imaging tools to assess cognitive impairment and to track microglia activation. Understanding the role of microglia in cognitive impairment and how it can be prevented may be a promising contribution to innovative therapeutic strategies that culminate in the improvement of MS patients' life quality.

S100B Impairs Oligodendrogenesis and Myelin Repair Following Demyelination Through RAGE Engagement.

Increased expression of S100B and its specific receptor for advanced glycation end products (RAGE) has been described in patients with multiple sclerosis (MS), being associated with an active demyelinating process. We previously showed that a direct neutralization of S100B reduces lysophosphatidylcholine (LPC)-induced demyelination and inflammation using an ex vivo demyelinating model. However, whether S100B actions occur through RAGE and how oligodendrogenesis and remyelination are affected are not clarified. To evaluate the role of the S100B-RAGE axis in the course of a demyelinating insult, organotypic cerebellar slice cultures (OCSC) were demyelinated with LPC in the presence or absence of RAGE antagonist FPS-ZM1. Then, we explored the effects of the S100B-RAGE axis inhibition on glia reactivity and inflammation, myelination and neuronal integrity, and on oligodendrogenesis and remyelination. In the present study, we confirmed that LPC-induced demyelination increased S100B and RAGE expression, while RAGE antagonist FPS-ZM1 markedly reduced their content and altered RAGE cellular localization. Furthermore, FPS-ZM1 prevented LPC-induced microgliosis and astrogliosis, as well as NF-κB activation and pro-inflammatory cytokine gene expression. In addition, RAGE antagonist reduced LPC-induced demyelination having a beneficial effect on axonal and synaptic protein preservation. We have also observed that RAGE engagement is needed for LPC-induced oligodendrocyte (OL) maturation arrest and loss of mature myelinating OL, with these phenomena being prevented by FPS-ZM1. Our data suggest that increased levels of mature OL in the presence of FPS-ZM1 are related to increased expression of microRNAs (miRs) associated with OL differentiation and remyelination, such as miR-23a, miR-219a, and miR-338, which are defective upon LPC incubation. Finally, our electron microscopy data show that inhibition of the S100B-RAGE axis prevents axonal damage and myelin loss, in parallel with enhanced functional remyelination, as observed by the presence of thinner myelin sheaths when compared with Control. Overall, our data implicate the S100B-RAGE axis in the extent of myelin and neuronal damage, as well as in the inflammatory response that follows a demyelinating insult. Thus, prevention of RAGE engagement may represent a novel strategy for promoting not only inflammatory reduction but also neuronal and myelin preservation and/or remyelination, improving recovery in a demyelinating condition as MS.

Microglial Phagocytosis-Rational but Challenging Therapeutic Target in Multiple Sclerosis.

Multiple sclerosis (MS) is the most common autoimmune and demyelinating disease of the central nervous system (CNS), characterized, in the majority of cases, by initial relapses that later evolve into progressive neurodegeneration, severely impacting patients' motor and cognitive functions. Despite the availability of immunomodulatory therapies effective to reduce relapse rate and slow disease progression, they all failed to restore CNS myelin that is necessary for MS full recovery. Microglia are the primary inflammatory cells present in MS lesions, therefore strongly contributing to demyelination and lesion extension. Thus, many microglial-based therapeutic strategies have been focused on the suppression of microglial pro-inflammatory phenotype and neurodegenerative state to reduce disease severity. On the other hand, the contribution of myelin phagocytosis advocating the neuroprotective role of microglia in MS has been less explored. Indeed, despite the presence of functional oligodendrocyte precursor cells (OPCs), within lesioned areas, MS plaques fail to remyelinate as a result of the over-accumulation of myelin-toxic debris that must be cleared away by microglia. Dysregulation of this process has been associated with the impaired neuronal recovery and deficient remyelination. In line with this, here we provide a comprehensive review of microglial myelin phagocytosis and its involvement in MS development and repair. Alongside, we discuss the potential of phagocytic-mediated therapeutic approaches and encourage their modulation as a novel and rational approach to ameliorate MS-associated pathology.

Cyanine-Like Boronic Acid-Derived Salicylidenehydrazone Complexes (Cy-BASHY) for Bioimaging Applications.

Boronic acid-derived salicylidenehydrazone complex (BASHY) dyes with a polymethine backbone were designed to yield efficient red-emitting and two-photon absorbing fluorophores that can be used as markers for astrocytes. The dyes are chemically stable in aqueous solution and do not undergo photodecomposition. Their photophysical properties can be electronically fine-tuned and thereby adapted to potentially different imaging situations and requirements.

Frailty-A promising concept to evaluate disease vulnerability.

With the emergence of diseases, people become frailer and are expected to be less tolerant of adverse outcomes. Frailty was first described to explain the variability in life expectancy in individuals of the same age. Nowadays, it is described as a syndrome and as a state. It is used to explain the heterogeneity of people not only in their responses to biological ageing but also in their responses to illness. In this review, we explore the role of frailty both in age-related diseases, including dementia, cancer and cardiovascular disease, and in non-age-related diseases, such as Human Immunodeficiency Virus. We describe how high levels of frailty in such disorders predict worse outcomes and play a direct role in disease progression and in prognostic prediction. Overall, the potential for frailty to predict adverse health outcomes among young people as well as in non-age-related diseases is an evolving topic. Understanding how frailty contributes to poor health and how it can be modified to prevent or delay disease progression will ultimately enhance quality of life in affected individuals.

Enhanced cognitive performance in experimental autoimmune encephalomyelitis mice treated with dimethyl fumarate after the appearance of disease symptoms.

In multiple sclerosis (MS), cognitive dysfunction is common but difficult to treat. We analyzed the impact of dimethyl fumarate, an MS drug with neuroprotective properties, in spatial memory performance in a mouse model of MS and looked for structural correlates in the hippocampus. Treated mice presented better cognitive performance which was not associated with structural hippocampal damage but with decreased demyelination in the fimbria. Dimethyl fumarate, even if initiated after hindlimb paralysis, ameliorated memory deficits in the MS mouse model due, at least in part, to its positive impact in the demyelination of the main hippocampal output pathway.