Targeting Systemic Innate Immune Cells as a Therapeutic Avenue for Alzheimer Disease.

Alzheimer disease (AD) is the first progressive neurodegenerative disease worldwide, and the disease is characterized by an accumulation of amyloid in the brain and neurovasculature that triggers cognitive decline and neuroinflammation. The innate immune system has a preponderant role in AD. The last decade, scientists focused their efforts on therapies aiming to modulate innate immunity. The latter is of great interest, since they participate to the inflammation and phagocytose the amyloid in the brain and blood vessels. We and others have developed pharmacological approaches to stimulate these cells using various ligands. These include toll-like receptor 4, macrophage colony stimulating factor, and more recently nucleotide-binding oligomerization domain-containing 2 receptors. This review will discuss the great potential to take advantage of the innate immune system to fight naturally against amyloid ß accumulation and prevent its detrimental consequence on brain functions and its vascular system. SIGNIFICANCE STATEMENT: The focus on amyloid ß removal from the perivascular space rather than targeting CNS plaque formation and clearance represents a new direction with a great potential. Small molecules able to act at the level of peripheral immunity would constitute a novel approach for tackling aberrant central nervous system biology, one of which we believe would have the potential of generating a lot of interest.

Gender differences in COVID-19 attitudes and behavior: Panel evidence from eight countries.

The initial public health response to the breakout of COVID-19 required fundamental changes in individual behavior, such as isolation at home or wearing masks. The effectiveness of these policies hinges on generalized public obedience. Yet, people's level of compliance may depend on their beliefs regarding the pandemic. We use original data from two waves of a survey conducted in March and April 2020 in eight Organisation for Economic Co-operation and Development countries (n = 21,649) to study gender differences in COVID-19-related beliefs and behaviors. We show that women are more likely to perceive COVID-19 as a very serious health problem, to agree with restraining public policy measures, and to comply with them. Gender differences in attitudes and behavior are sizable in all countries. They are accounted for neither by sociodemographic and employment characteristics nor by psychological and behavioral factors. They are only partially mitigated for individuals who cohabit or have direct exposure to the virus. We show that our results are not due to differential social desirability bias. This evidence has important implications for public health policies and communication on COVID-19, which may need to be gender based, and it unveils a domain of gender differences: behavioral changes in response to a new risk.

Herpes Simplex Virus 1 Infection Does Not Increase Amyloid-ß Pathology in APP/PS1 Mice.

Using APP/PS1 mice that overproduce amyloid-ß (Aß) peptides, we investigated whether intranasal infection with a neurovirulent clinical strain of herpes simplex virus 1 (HSV-1) before Aß deposition could accelerate or increase Alzheimer's disease-like pathology. After HSV-1 infection, APP/PS1 mice presented a similar disease as wild type animals based on body weight changes, clinical symptoms, and survival rates. The number and volume of Aß plaques, the number of microglia, and the percentages of circulating monocyte subsets were similar in APP/PS1 mice infected or not with HSV-1. Thus, intranasal infection with HSV-1 does not alter Aß pathology in this mouse model.

Inhibiting nighttime melatonin and boosting cortisol increase patrolling monocytes, phagocytosis, and myelination in a murine model of multiple sclerosis.

Conflicting results on melatonin synthesis in multiple sclerosis (MS) have been reported due to variabilities in patient lifestyles, which are not considered when supplementing melatonin. Since melatonin acts through its receptors, we identified melatonin receptors in oligodendrocytes (OLs) in the corpus callosum, where demyelination occurs; the subventricular zone, where neural stem/progenitor cells (NSPCs) are located; and the choroid plexus, which functions as a blood-cerebrospinal fluid barrier. Moreover, using chimeric mice, resident macrophages were found to express melatonin receptors, whereas bone marrow-derived macrophages lost this expression in the demyelinated brain. Next, we showed that cuprizone-fed mice, which is an MS model, tended to have increased melatonin levels. While we used different approaches to alter the circadian rhythm of melatonin and cortisol, only the constant light approach increased NSPC proliferation and differentiation to oligodendrocyte precursor cells (OPCs), OPCs maturation to OLs and recruitment to the site of demyelination, the number of patrolling monocytes, and phagocytosis. In contrast, constant darkness and exogenous melatonin exacerbated these events and amplified monocyte infiltration. Therefore, melatonin should not be considered a universal remedy, as is currently claimed. Our data emphasize the importance of monitoring melatonin/cortisol oscillations in each MS patient by considering diet and lifestyle to avoid melatonin overdose.

Addressing vaccine hesitancy: experimental evidence from nine high-income countries during the COVID-19 pandemic.

We study the impact of public health messages on intentions to vaccinate and vaccination uptakes, especially among hesitant groups. We performed an experiment comparing the effects of egoistic and altruistic messages on COVID-19 vaccine intentions and behaviour. We administered different messages at random in a survey of 6379 adults in December 2020, following up with participants in the nationally representative survey Citizens' Attitudes Under COVID-19 Project covering nine high-income countries (Australia, Austria, France, Germany, Italy, New Zealand, Sweden, the UK and the USA). Four alternative interventions were tested, based on narratives of (1) self-protection, (2) protecting others, (3) reducing health risks and (4) economic protection. We measure vaccination intentions in the December 2020 survey and elicit actual vaccination behaviour by respondents in the June/July 2021 survey. Messages conveying self-protection had no effect on vaccine intentions but altruistic messages, emphasising protecting other individuals (0.022, 95% CI -0.004 to 0.048), population health (0.030, 95% CI 0.003 to 0.056) and the economy (0.038, 95% CI 0.013 to 0.064) had substantially stronger effects. These effects were stronger in countries experiencing high COVID-19 mortality (Austria, France, Italy, Sweden, the UK and the USA), where health risks may have been more salient, but weaker and, in several cases, not significant where mortality was low (Australia, Germany and New Zealand). On follow-up at 6 months, these brief communication interventions corresponded to substantially higher vaccination uptake. Our experiments found that commonly employed narratives around self-protection had no effect. However, altruistic messages about protecting individuals, population health and the economy had substantially positive and enduring effects on increasing vaccination intentions. Our results can help structure communication campaigns during pandemics and are likely to generalise to other vaccine-preventable epidemics.

Practice makes the model: A critical review of stormwater green infrastructure modelling practice.

Green infrastructures (GIs) have in recent decades emerged as sustainable technologies for urban stormwater management, and numerous studies have been conducted to develop and improve hydrological models for GIs. This review aims to assess current practice in GI hydrological modelling, encompassing the selection of model structure, equations, model parametrization and testing, uncertainty analysis, sensitivity analysis, the selection of objective functions for model calibration, and the interpretation of modelling results. During a quantitative and qualitative analysis, based on a paper analysis methodology applied across a sample of 270 published studies, we found that the authors of GI modelling studies generally fail to justify their modelling choices and their alignments between modelling objectives and methods. Some practices, such as uncertainty analysis, were also found to be limited, despite their necessity being widely acknowledged by the scientific community and their application in other fields. In order to improve current GI modelling practice, the authors suggest the following: i) a framework, called STAMP, designed to promote the standardisation of the documentation of GI modelling studies, and ii) improvements in modelling tools for facilitating good practices, iii) the sharing of data for better model testing, iv) the evaluation of the suitability of hydrological equations for GI application, v) the publication of clear statements regarding model limitations and negative results.

Muramyl Dipeptide Administration Delays Alzheimer's Disease Physiopathology via NOD2 Receptors.

Alzheimer's disease (AD) is the most common form of dementia in the world. The prevalence is steadily increasing due to an aging population and the lack of effective treatments. However, modulation of innate immune cells is a new therapeutic avenue, which is quite effective at delaying disease onset and improving cognitive decline. METHODS: We studied the effect of the NOD2 receptor ligand muramyl dipeptide (MDP) on the modulation of the innate immune cells, namely patrolling monocytes and microglia. We administrated MDP once a week for 3 months in an APPswe/PS1 mouse model in both sexes. We started the treatment at 3 months before plaque formation and evaluated its effects at 6 months. RESULTS: We showed that the MDP injections delay cognitive decline in both sexes via different mechanisms and protect the blood brain barrier (BBB). In males, MDP triggers the sink effect from the BBB, leading to a diminution in the amyloid load in the brain. This phenomenon is underlined by the increased expression of phagocytosis markers such as TREM2, CD68, and LAMP2 and a higher expression of ABCB1 and LRP1 at the BBB level. The beneficial effect seems more restricted to the brain in females treated with MDP, where microglia surround amyloid plaques and prevent the spreading of amyloid peptides. This phenomenon is also associated with an increase in TREM2 expression. Interestingly, both treated groups showed an increase in Arg-1 expression compared to controls, suggesting that MDP modulates the inflammatory response. CONCLUSION: These results indicate that stimulation of the NOD2 receptor in innate immune cells is a promising therapeutic avenue with potential different mechanisms between males and females.

Multifocal Cerebral Microinfarcts Modulate Early Alzheimer's Disease Pathology in a Sex-Dependent Manner.

Alzheimer's disease (AD) constitutes a major cause of dementia, affecting more women than men. It is characterized by amyloid-ß (Aß) deposition and neurofibrillary tangles (NFTs) formation, associated with a progressive cognitive decline. Evidence indicates that AD onset increases the prevalence of cerebral microinfarcts caused by vascular pathologies, which occur in approximately in half of AD patients. In this project, we postulated that multifocal cerebral microinfarcts decisively influence early AD-like pathology progression in a sex dependent manner in young APP/PS1 mice. For this purpose, we used a novel approach to model multifocal microinfarcts in APP/PS1 mice via the sporadic occlusions of the microvasculature. Our findings indicate that microinfarcts reduced Aß deposits without affecting soluble Aß levels in the brain of male and female APP/PS1 mice, while causing rapid and prolonged cognitive deficits in males, and a mild and transient cognitive decline in females. In male APP/PS1 mice, microinfarcts triggered an acute hypoperfusion followed by a chronic hyperperfusion. Whereas in female APP/PS1 mice, microinfarcts caused an acute hypoperfusion, which was recovered in the chronic phase. Microinfarcts triggered a robust microglial activation and recruitment of peripheral monocytes to the lesion sites and Aß plaques more potently in female APP/PS1 mice, possibly accounting for the reduced Aß deposition. Finally, expression of Dickkopf-1 (DKK1), which plays a key role in mediating synaptic and neuronal dysfunction in AD, was strongly induced at the lesion sites of male APP/PS1 mice, while its expression was reduced in females. Our findings suggest that multifocal microinfarcts accelerate AD pathology more potently in young males compared to young females independently upon Aß pathology via modulation of neurovascular coupling, inflammatory response, and DKK1 expression. Our results suggest that the effects of microinfarcts should be taken into consideration in AD diagnosis, prognosis, and therapies.

Triggering Innate Immune Receptors as New Therapies in Alzheimer's Disease and Multiple Sclerosis.

Multiple sclerosis and Alzheimer's disease are two complex neurodegenerative diseases involving the immune system. So far, available treatments provide at best mild improvements to patients' conditions. For decades now, a new set of molecules have been used to modulate and regulate the innate immunity in these pathologies. Most studies have been carried out in rodents and some of them have reported tremendous beneficial effects on the disease course. The modulation of innate immune cells is of great interest since it provides new hope for patients. In this review, we will briefly overview the therapeutic potential of some molecules and receptors in multiple sclerosis and Alzheimer's disease and how they could be used to exploit new therapeutic avenues.

Conditional genetic deletion of CSF1 receptor in microglia ameliorates the physiopathology of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia in the world. Microglia are the innate immune cells of CNS; their proliferation, activation, and survival in pathologic and healthy brain have previously been shown to be highly dependent on CSF1R. METHODS: Here, we investigate the impact of such receptor on AD etiology and microglia. We deleted CSF1R using Cre/Lox system; the knockout (KO) is restricted to microglia in the APP/PS1 mouse model. We induced the knockout at 3 months old, before plaque formation, and evaluated both 6- and 8-month-old groups of mice. RESULTS: Our findings demonstrated that CSF1R KO did not impair microglial survival and proliferation at 6 and 8 months of age in APP cKO compared to their littermate-control groups APPSwe/PS1. We have also shown that cognitive decline is delayed in CSF1R-deleted mice. Ameliorations of AD etiology are associated with a decrease in plaque volume in the cortex and hippocampus area. A compensating system seems to take place following the knockout, since TREM2/ß-Catenin and IL-34 expression are significantly increased. Such a compensatory mechanism may promote microglial survival and phagocytosis of Aß in the brain. CONCLUSIONS: Our results provide new insights on the role of CSF1R in microglia and how it interacts with the TREM2/ß-Catenin and IL-34 system to clear Aß and ameliorates the physiopathology of AD.

The Intellicage system provides a reproducible and standardized method to assess behavioral changes in cuprizone-induced demyelination mouse model.

BACKGROUND: Multiple sclerosis is a neurodegenerative disorder characterized by myelin loss in the brain parenchyma. To mimic the disease, mice are fed a cuprizone-supplemented diet for 5 weeks, which leads to demyelination of white and grey matter regions, with the corpus callosum being the most susceptible to cuprizone intoxication. Although this model is highly exploited, classical behavioural tests showed inconsistent results. OBJECTIVE: In our study, we aimed to use the automated system Intellicage to phenotype the behaviour of cuprizone-fed mice. METHODS: Mice were continuously monitored during the 5 weeks of intoxication in their home cages, with minimal interference from the experimenter. Mice were assessed for spontaneous activity, fine movements, and impulsivity. RESULTS: Consistently, cuprizone-fed mice showed reduced activity and impulsivity throughout the test period. These behavioral results were confirmed by repeating the battery of behavioral tests in a second cohort of cuprizone-fed mice. Our results suggest that the behavioural phenotyping of cuprizone-fed mice using Intellicage is reproducible and sensitive enough to detect changes normally missed in standard behavioral test batteries. CONCLUSION: Using a reproducible and standardized method to assess behavioral changes in mice intoxicated with cuprizone is crucial to better understand the disease as well as the functional outcome of treatments.

Beneficial Roles of Microglia and Growth Factors in MS, a Brief Review.

Microglia are the brain resident immune cells; they can produce a large variety of growth factors (GFs) to prevent neuronal damages and promote recovery. In neurodegenerative diseases, microglia can play both benefic and deleterious roles, depending on different factors and disease context. In multiple sclerosis, microglia are involved in both demyelination (DM) and remyelination (RM) processes. Recent studies suggest a beneficial role of microglia in regenerative processes. These include the regenerative development of myelin after DM. This review gives an overlook of how microglia and GFs can influence the RM properties.

Role of Macrophage Colony-Stimulating Factor Receptor on the Proliferation and Survival of Microglia Following Systemic Nerve and Cuprizone-Induced Injuries.

Microglia are the innate immune cells of the CNS and their proliferation, activation, and survival have previously been shown to be highly dependent on macrophage colony-stimulating factor receptor (CSF1R). Here we investigated the impact of the receptor in such processes using two different models of nerve injuries, namely hypoglossal axotomy and cuprizone-induced demyelination. Both models are associated with a robust microgliosis. The role of CSF1R was investigated using the gene deletion Cre/Lox system, which allows the conditional knock-out following tamoxifen administration. We found that after 5 weeks of cuprizone diet that CSF1R suppression caused a significant impairment of microglia function. A reduced microgliosis was detected in the corpus collosum of CSF1R knock-out mice compared to controls. In contrast to cuprizone model, the overall number of Iba1 cells was unchanged at all the times evaluated following hypoglossal axotomy in WT and cKO conditions. After nerve lesion, a tremendous proliferation was noticed in the ipsilateral hypoglossal nucleus to a similar level in both knock-out and wild-type groups. We also observed infiltration of bone-marrow derived cells specifically in CSF1R-deficient mice, these cells tend to compensate the CSF1R signaling pathway suppression in resident microglia. Taking together our results suggest a different role of CSF1R in microglia depending on the model. In the pathologic context of cuprizone-induced demyelination CSF1R signaling pathway is essential to trigger proliferation and survival of microglia, while this is not the case in a model of systemic nerve injury. M-CSF/CSF1R is consequently not the unique system involved in microgliosis following nerve damages.

Microglia Purinoceptor P2Y6: An Emerging Therapeutic Target in CNS Diseases.

The purinergic receptor P2Y6 is expressed in immune cells, including the microglia that are implicated in neurological disorders. Its ligand, UDP, is a signaling molecule that can serve as an "find-me" signal when released in significant quantities by damaged/dying cells. The binding of UDP by P2Y6R leads to the activation of different biochemical pathways, depending on the disease context and the pathological environment. Generally, P2Y6R stimulates phagocytosis. However, whether or not phagocytosis coincides with cell activation or the secretion of pro-inflammatory cytokines needs further investigation. The current review aims to discuss the various functions of P2Y6R in some CNS disorders. We present evidence that P2Y6R may have a detrimental or beneficial role in the nervous system, in the context of neurological pathologies, such as ischemic stroke, Alzheimer's disease, Parkinson's disease, radiation-induced brain injury, and neuropathic pain.

Sigma-borane complexes of iridium: synthesis and structural characterization.

Reaction of NaBH4 with (tBuPOCOP)IrHCl affords the previously reported complex (tBuPOCOP)IrH2(BH3) (1) (tBuPOCOP = kappa(3)-C6H3-1,3-[OP(tBu)2]2). The structure of 1 determined from neutron diffraction data contains a B-H sigma-bond to iridium with an elongated B-H bond distance of 1.45(5) A. Compound 1 crystallizes in the space group P1 (Z = 2) with a = 8.262 (5) A, b = 12.264 (5) A, c = 13.394 (4) A, and V = 1256.2 (1) A(3) (30 K). Complex 1 can also be prepared by reaction of BH3 x THF with (tBuPOCOP)IrH2. Reaction of (tBuPOCOP)IrH2 with pinacol borane gave initially complex 2, which is assigned a structure analogous to that of 1 based on spectroscopic measurements. Complex 2 evolves H2 at room temperature leading to the borane complex 3, which is formed cleanly when 2 is subjected to dynamic vacuum. The structure of 3 has been determined by X-ray diffraction and consists of the (tBuPOCOP)Ir core with a sigma-bound pinacol borane ligand in an approximately square planar complex. Compound 3 crystallizes in the space group C2/c (Z = 4) with a = 41.2238 (2) A, b = 11.1233 (2) A, c = 14.6122 (3) A, and V = 6700.21 (19) A(3) (130 K). Reaction of (tBuPOCOP)IrH2 with 9-borobicyclononane (9-BBN) affords complex 4. Complex 4 displays (1)H NMR resonances analogous to 1 and exists in equilibrium with (tBuPOCOP)IrH2 in THF solutions.

Coordination of aminoborane, NH(2)BH(2), dictates selectivity and extent of H(2) release in metal-catalysed ammonia borane dehydrogenation.

In situ(11)B NMR monitoring, computational modeling, and external trapping studies show that selectivity and extent of H(2) release in metal-catalysed dehydrogenation of ammonia borane, NH(3)BH(3), are determined by coordination of reactive aminoborane, NH(2)BH(2), to the metal center.

New Therapeutic Avenues of mCSF for Brain Diseases and Injuries.

Macrophage colony-stimulating factor (mCSF) is a cytokine known to promote the recruitment of macrophages inducing the release of CCL2, a chemokine mobilizing monocytes to sites of inflammation. Additionally, it induces microglia/macrophage proliferation and the polarization of these cells towards a M2-like phenotype, impairing their ability to release pro-inflammatory factors and toxic mediators, while favoring the release of mediators promoting tissue repair. Another important player is the mCSF receptor CSFR1, which is highly expressed in monocytes, macrophages and microglia. Here, we discuss the new interesting therapeutic avenue of the mCSF/CSFR1 axis on brain diseases. More specifically, mCSF cascade might stimulate the survival/proliferation of oligodendrocytes, enhance the immune response as well as modulate the release of growth factors and the phagocytic activity of immune cells to remove myelin debris and toxic proteins from the brain.

Knowledge about tuberculosis and infection prevention behavior: A nine city longitudinal study from India.

BACKGROUND: Improving patients' tuberculosis (TB) knowledge is a salient component of TB control strategies. Patient knowledge of TB may encourage infection prevention behaviors and improve treatment adherence. The purpose of this study is to examine how TB knowledge and infection prevention behaviors change over the course of treatment. METHODS: A matched patient-health worker dataset (n = 6,031) of publicly treated TB patients with NGO-provided treatment support health workers was compiled in nine Indian cities from March 2013 to September 2014. At the beginning and end of TB treatment, patients were asked about their knowledge of TB symptoms, transmission, and treatment and infection prevention behaviors. RESULTS: Patients beginning TB treatment (n = 3,424) demonstrated moderate knowledge of TB; 52.5% (50.8%, 54.2%) knew that cough was a symptom of TB and 67.2% (65.6%, 68.7%) knew that TB was communicable. Overall patient knowledge was significantly associated with literacy, education, and income, and was higher at the end of treatment than at the beginning (3.7%, CI: 3.02%, 4.47%). Infection prevention behaviors like covering a cough (63.4%, CI: 61.2%, 65.0%) and sleeping separately (19.3%, CI: 18.0%, 20.7%) were less prevalent. The age difference between patient and health worker as well as a shared language significantly predicted patient knowledge and adherence to infection prevention behaviors. CONCLUSIONS: Social proximity between health worker and patients predicted greater knowledge and adherence to infection prevention behaviors but the latter rate remains undesirably low.