Microglia-complement implication and structural-functional synaptic characterization in the hippocampus of early Experimental Autoimmune Encephalomyelitis (EAE) model of Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system (CNS) in which the immune system plays a central role to drive pathology. In addition to motor and sensory symptoms, memory impairment is reported in MS patients in early stage of the disease and in rodent models prior to the disease onset. The synaptic pruning is a physiological developmental mechanism, crucial for brain connectivity in which the complement components C1q-C3 and the phagocytic receptors expressed by microglia, C3R and Trem2, have been implicated. A reactivation of similar mechanism may be one of the central causes of the synapses loss in neurodegenerative disorders including MS and might explain the early synaptic changes occurring within the hippocampus. In this thesis, we have analyzed the demyelination process, the classical complement components activation and the synapse-microglia interaction in the hippocampus of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We have focused on the earliest stage (i.e. after induction), when motor symptoms are still not observed. Furthermore we have investigated the role of microglia phagocytic receptors Trem2 and C3R and the classical complement component C3 in the disease progression. Following immunohistochemical analysis, we have found no demyelination or microglial activation, as well as unaltered complement components expression levels. In addition, we have found no changes in the synaptic density within the hippocampus of the asymptomatic EAEmice, compared to their controls. Notably, we have found an increased VGAT expression in the CA1 region of the hippocampus at day 8 post-immunization which reflects a subtle alteration of inhibitory neurotransmission but whose significance is still unclear. Moreover, electrophysiological examination of the hippocampal synaptic transmission and plasticity did not establish any changes on synaptic function at the earliest stage after induction. However, genetic deletion of complement protein C3 and its receptor subunit CD11b reduces motor symptom severity in EAE mouse but has no effect on the disease onset. We then sought to determine the role of Trem2 receptor on clinical motor score severity. Unexpectedly, inducing EAE in Trem2 knockout mice is associated with a reduction in clinical score and in the demyelination progression. To sum up, we believe that hippocampus synaptic degeneration occurs late in the disease, when motor symptoms are well established. Overall, we have confirmed the role of classical complement components C3 and C3R in the EAE progression and disease manifestation, and we have identified Trem2 receptor as a potential anti-inflammatory target for a disease modifying therapy

Microbe-assisted seedling crop improvement by a seaweed extract to address fucalean forest restoration

In the Mediterranean, Cystoseira sensu lato (s.l.) (Phaeophyceae) forests have sharply declined and restoration measures are needed to compensate for the loss. Assisted regeneration through the outplanting of seedlings grown ex-situ has proven to be a sustainable option. Optimizing mesocosm culture can maximize survival of the most critical embryonic stages and reduce long-term maintenance costs. Host-microbiome interactions could also play a crucial role in seedling development and welfare. In this context, we aimed to advance a cultivation protocol that stimulates the growth and fitness of Ericaria amentacea (Phaeophyceae) seedlings and identify the associated microbial biofilm communities. Seedlings were cultured in 6 treatments [i.e., filtered seawater (SW, C, Control), von Stoch-enriched SW (VS), VS + algal extract (VSA), algal extract-enriched SW: A1< A2< A3]. After the field, A2 seedlings had the highest cover (1372 ± 53.66 mm2), which was 1.8 and 1.9 times greater than in VS and VSA, respectively. The addition of the algal extract and nutrients significantly affected the structure and composition of the microbial community that shifted over time in each culture medium. We identified a treatment-specific microbial fingerprint. After the mesocosm phase, A2 was characterized by 4 unique taxa: Postechiella, Winogradskyella, Roseovarius and Arenibacter (Bacteria). Given the success of A2 seedlings, we propose the probiotic consortia candidates characterized by the unique treatment-taxa in conjunction with the shared taxon Psychroserpens (Bacteria, present in A1, A2, VSA, VS) and the reminder community. Within the holobiont concept, the effect of algal extract or nutrients on the algae and/or biofilm could have important consequences for tuning the overall interaction networks. Our study has shown that macroalgal restoration could benefit from both the use of commercial algal extract and tailored nutrient enrichment in ex-situ cultures and the identification of probiotic consortia candidates that promote seedling growth

In Vitro Functional Characterization of Type-I Taste Bud Cells as Monocytes/Macrophages-like Which Secrete Proinflammatory Cytokines

The sense of taste determines the choice of nutrients and food intake and, consequently, influences feeding behaviors. The taste papillae are primarily composed of three types of taste bud cells (TBC), i.e., type I, type II, and type III. The type I TBC, expressing GLAST (glutamate-–aspartate transporter), have been termed as glial-like cells. We hypothesized that these cells could play a role in taste bud immunity as glial cells do in the brain. We purified type I TBC, expressing F4/80, a specific marker of macrophages, from mouse fungiform taste papillae. The purified cells also express CD11b, CD11c, and CD64, generally expressed by glial cells and macrophages. We further assessed whether mouse type I TBC can be polarized toward M1 or M2 macrophages in inflammatory states like lipopolysaccharide (LPS)-triggered inflammation or obesity, known to be associated with low-grade inflammation. Indeed, LPS-treatment and obesity state increased TNFα, IL-1β, and IL-6 expression, both at mRNA and protein levels, in type I TBC. Conversely, purified type I TBC treated with IL-4 showed a significant increase in arginase 1 and IL-4. These findings provide evidence that type I gustatory cells share many features with macrophages and may be involved in oral inflammation

Stress as risk factor for Alzheimer's disease

Prolonged stress predisposes susceptible individuals to a number of physiological disorders including cardiovascular disease, obesity and gastrointestinal disorders, as well as psychiatric and neurodegenerative disorders. Preclinical studies have suggested that manipulation of the glucocorticoid milieu can trigger cellular, molecular and behavioral derangement resembling the hallmarks of Alzheimer's Disease (AD). For example, stress or glucocorticoid administration can increase amyloid ß precursor protein and tau phosphorylation which are involved in synaptic dysfunction and neuronal death associated with AD. Although since AD was first described in 1906 at a conference in Tubingen, Germany by Alois Alzheimer our knowledge of neuropathological and neurochemical alterations of AD has been impressively increased, at present, pharmacotherapy is symptomatic at best and has no influence on the progression of the disorder. It is generally believed that most of the drugs developed as disease modifiers have failed in clinical trials because treatment started too late, i.e., after the clinical onset of AD. Because AD pathology begins several years prior to the clinical diagnosis, it is imperative to identify subjects at high risk to develop the disorder. Consequently, the search for putative risk factors has gained importance. ApoE4, diabetes/metabolic syndrome, cardiovascular disorders, and a low cognitive reserve are established risk factors for AD. The focus of this review is on stress and glucocorticoids as potential factors increasing the risk to develop AD

Pharmacological targeting of microglia dynamics in Alzheimer's disease: Preclinical and clinical evidence

Numerous clinical trials of anti-amyloid agents for Alzheimer's disease (AD) were so far unsuccessful thereby challenging the validity of the amyloid hypothesis. This lack of progress has encouraged researchers to investigate alternative mechanisms in non-neuronal cells, among which microglia represent nowadays an attractive target. Microglia play a key role in the developing brain and contribute to synaptic remodeling in the mature brain. On the other hand, the intimate relationship between microglia and synapses led to the so-called synaptic stripping hypothesis, a process in which microglia selectively remove synapses from injured neurons. Synaptic stripping, along with the induction of a microglia-mediated chronic neuroinflammatory environment, promote the progressive synaptic degeneration in AD. Therefore, targeting microglia may pave the way for a new disease modifying approach. This review provides an overview of the pathophysiological roles of the microglia cells in AD and describes putative targets for pharmacological intervention. It also provides evidence for microglia-targeted strategies in preclinical AD studies and in early clinical trials

Targeting Synaptic Plasticity in Experimental Models of Alzheimer's Disease

Long-term potentiation (LTP) and long-term depression (LTD) of hippocampal synaptic transmission represent the principal experimental models underlying learning and memory. Alterations of synaptic plasticity are observed in several neurodegenerative disorders, including Alzheimer's disease (AD). Indeed, synaptic dysfunction is an early event in AD, making it an attractive therapeutic target for pharmaceutical intervention. To date, intensive investigations have characterized hippocampal synaptic transmission, LTP, and LTD in in vitro and in murine models of AD. In this review, we describe the synaptic alterations across the main AD models generated so far. We then examine the clinical perspective of LTP/LTD studies and discuss the limitations of non-clinical models and how to improve their predictive validity in the drug discovery process

Temporal and spatial distribution of dorcas and slender‐horned gazelles in a Saharan habitat

Saharan ungulates have suffered from poaching across their range leading to population declines. Low abundance and habitat inaccessibility have limited the availability of empirical data on desert ungulate ecology in the wild. Our objective was to evaluate temporal and spatial distribution, and home-range sizes of wild dorcas gazelles (Gazella dorcas) and slender-horned gazelles (Gazella leptoceros) under natural conditions using observations from 14,398 camera-days collected between April 2019 and October 2021 in the 7,700-ha fenced area of Jbil National Park (Jbil NP), Tunisia. We individually identified gazelles in Jbil NP using unique horn morphology. Both gazelle species exhibited nocturnal activity patterns in summer, but diurnal activity patterns dominated in winter. We also detected both species more frequently in the plains than in mountains. Water presence was influential in determining distribution only for dorcas gazelles. Minimum convex polygons (MCPs) were 2,062 ha for both the male and female of the most frequently detected dorcas gazelle pair and 1,527 ha for another solitary male. For slender-horned gazelles, MCPs were 2,280 ha and 2,041 ha, respectively, for a male and a female detected in Jbil NP. The decline and rarity of gazelles in the Sahara Desert have limited the sample size of our observed populations. Our study provides hitherto unknown data on wild populations of rapidly declining gazelle species and contributes to ongoing conservation efforts.</p