Welcome to the IBRO 2023 Interactive Programme

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The worldwide life expectancy has dramatically increased in the last decades, together with an increment in the age-related pathologies, such as neurodegenerative diseases or cardiovascular disorders. Along physiological brain aging, several cellular and molecular changes are detected, even in the absence of pathology, including neuroinflammation, decrease in synaptic connections, impaired lipid homeostasis, etc. Therefore, a better characterization of the age-related changes in different brain areas is of particular relevance to understand early neurodegenerative events and the development of early diagnostic tools and pharmacological interventions. In this sense, the availability of adequate experimental models is of vital importance. The O. degus has been proposed as an interesting experimental model for aging and neurodegeneration research. Here, we characterized the hippocampal-related neuroinflammatory processes and the lipid changes in different brain areas (prefrontal cortex, cortex, striatum and cerebellum) along aging with a sex perspective in the O. degus. We found that, in all dorsal hippocampal subareas analyzed, neuroinflammation (astroglia and microglia) was significantly increased in older animals, being the basal immunolabeling levels for microglia and astrocytes higher in males than in females. The changes observed during aging were region-specific, those in glycosphingolipids being common to all regions. The greatest sex-associated differences were found in gangliosides at all ages, while sphingomyelin and sulfatides were significantly different when comparing males and females of senile age. Finally, given its key role in spatial memory circuits, lipid peroxidation was analyzed in the prefrontal cortex. We found that it was significantly increased along aging, males showing significant higher levels of lipid peroxidation than females. These results contribute to a better characterization of this model for aging research from the sex-differences approach and highlight that both variables are encouraged to be taken into account in the field of nerodegenerative diseases.

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Glial cells and neuroinflammation serve key roles, being relevant players in the pathophysiology of neuronal dysfunction and neurodegeneration. Little is known about the molecular mechanisms involved in neuron-microglia regulatory crosstalk, its changes in aging, and the potential involvement in the regulation of synaptic function, glia-mediated neuroprotection and -degeneration, or processes leading to CNS injury. Age-related changes in glial cell activation are relevant for neurodegenerative diseases. Those changes involve differences in glial cell activation and cell signaling depending on inflammatory and regulatory cytokines. They depend on various factors, including cytokines like TGFβ, and Scavenger Receptor A (SR-A), which participate in the regulation of glial cell activation, and the Fractalkine/CX3CR1 signaling involved in the regulation of microglia by neurons. We have evidence that aging-related changes result in the modification of glial cells regulation at various levels. Here, we will characterize and discuss age-dependent changes of various pathways in the brain of wild type (WT) and an inflammatory mouse model (knockout for scavenger receptor-A, SRA-KO). WT and SRA-KO mice of 3-6, 12- and 20-month-old were analyzed. To evaluate the effect of inflammation, mice were administered intraperitoneally 1 mg/kg LPS or vehicle. 24 hour later, the relative presence of various receptors was analyzed by qRT-PCR and western blot. Brain localization and distribution of receptors and signaling pathways were assessed by immunohistochemistry. We observed that changes on TGFβ, activation of inflammatory signaling pathways, SR-A and fractalkine were profoundly affected by aging, even in the absence of exogenous inflammatory conditions. Several changes are already observed at 12 months, including a 3-fold increase of Fractalkine compared with that of young mice, with predominance of the soluble fraction. Our findings suggest that aging favors the presence of Fractalkine in their soluble (cleaved) forms, promoting microglial inflammatory activation and a neuroinflammatory environment.

Support: Grant FONDECYT 1221028

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Glucose is the main energy substrate of the adult brain. When glucose is not really available, brain cells can use alternative energy sources such as monocarboxylates. Lactate, pyruvate and ketone bodies are monocarboxylates that have the facility to be exchanged and transported in different cells through monocarboxylate transporters (MCTs). Excitotoxicity due to excess glutamatergic neurotransmission is a well-studied phenomenon that has been linked to mechanisms of neuronal death that occur in some central nervous system disorders. In the first part of the work, to study whether mitochondrial energy dysfunction and oxidative stress might be involved in the excitotoxic process, we evaluated in two different in vivo models the protective effect of various energy substrates. We concluded that impaired energy metabolism plays a more important role than oxidative stress in excitotoxicity-mediated neurodegeneration. These first data led us to further study one of these energetic substrates, lactate. The formation, intercellular exchange and utilization of brain lactate have been linked to memory formation. However, the individual role of either neuronal or astroglial lactate transport for the acquisition and consolidation of information was incomplete. Using transgenic mice and a viral vector approach to decrease the expression of each transporter in a cell-specific manner within the dorsal hippocampus, we showed that both neuronal MCT2 and astroglial MCT4 are required for spatial information acquisition and retention (at 24 h post-training). In contrast, only neuronal MCT2 was shown to be required for long-term (7 days post training) memory formation. Interestingly, reduced MCT2 expression levels in mature neurons resulted in a heterologous effect as it blunts hippocampal neurogenesis associated with memory consolidation. These results suggest important but distinct contributions of both neuronal MCT2 and astroglial MCT4 in learning and memory processes, going beyond a simple passive role as alternative energy substrate suppliers or in waste product disposal.

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Astrocytes coordinate neuronal survival, synapse formation, pruning and function, participate in oligodendrocyte differentiation and integrate the neurovascular unit (NVU). Thus, early defects in astrocytes may contribute to the onset and progression of neurodevelopmental disorders. Here, we investigated the role of astrocytes on myelination and NVU function in glutaric acidemia type-I (GA-I) and maternal iron deficiency (ID). GA-I is an inherited neurometabolic disease characterized by striatal neurodegeneration, dismyelination, and vascular dysfunction upon cerebral accumulation of glutaric (GA) and 3-hydroxyglutaric acids, but through not fully understood mechanisms. The GA intracisternal injection to newborn rats, elicited increased proliferation of immature neurotoxic astrocytes at 1-5 days post-injection. At 12-30 days later, the striatum showed exacerbated ER stress and nuclear envelope swelling in oligodendrocytes; dismyelination and Evans Blue extravasation to the striatal parenchyma together with decreased aquaporin 4 (AQP4) and pericyte areas associated with small blood vessels. GA did not show direct effects on oligodendrocytes or pericytes but the conditioned media from GA-treated astrocytes had increased expression of pro-inflammatory cytokines and growth factors that might affect all neural cells. Concerning ID, this prevalent health problem irreversibly damages brain development and myelination, but NVU is poorly studied. Blood samples of rat pups from mothers fed with ID diet since embryonic day 5 till weaning, showed severe microcytic hypochromic anemia at 14 but not at 30 postnatal-day. However, at this age, the corpus callosum showed severe hypomyelination and immature astrocytes. In CA1 hippocampal region, ID AQP4+ capillaries were shorter than controls, had less AQP4 and fewer associated pericytes. Blood brain barrier disruption was not seen at the ages analyzed. Therefore, in the GA-I and ID models analyzed, macroglial cells and pericytes were directly or indirectly affected and could have deleterious effects on proper myelination or NVU function, thus contributing to systemic CNS damage.