S100B is a 21-kDa protein that is produced and secreted by astrocytes and widely used as a marker of brain injury in clinical and experimental studies. The majority of these studies are based on measurements in blood serum, assuming an associated increase in cerebrospinal fluid and a rupture of the blood–brain barrier (BBB). Moreover, extracerebral sources of S100B are often underestimated. Herein, we will review these interpretations and discuss the routes by which S100B, produced by astrocytes, reaches the circulatory system. We discuss the concept of S100B as an alarmin and its dual activity as an inflammatory and neurotrophic molecule. Furthermore, we emphasize the lack of data supporting the idea that S100B acts as a marker of BBB rupture, and the need to include the glymphatic system in the interpretations of serum changes of S100B. The review is also dedicated to valorizing extracerebral sources of S100B, particularly adipocytes. Furthermore, S100B per se may have direct and indirect modulating roles in brain barriers: on the tight junctions that regulate paracellular transport; on the expression of its receptor, RAGE, which is involved in transcellular protein transport; and on aquaporin-4, a key protein in the glymphatic system that is responsible for the clearance of extracellular proteins from the central nervous system. We hope that the data on S100B, discussed here, will be useful and that it will translate into further health benefits in medical practice.

Background: In the sporadic model of Alzheimer's disease (AD), induced by intracerebroventricular streptozotocin (STZ) administration, cognitive impairment is accompanied by specific astrocytic changes in the hippocampus prior to amyloid deposition. Objective: Hypothesizing that the synthesis of GABA, via MAO-B, contributes to ammonia elevation, thereby compromising antioxidant defense and ATP synthesis, and possibly contributing to cognitive damage, we determined the hippocampal levels of glutamine synthetase (GS), monoamine oxidase B (MAO-B) and other enzymes related to GABA metabolism. Methods: Immunoblotting and RT-PCR assays were carried out in hippocampal samples of Wistar rats, at 4 and 16 weeks post-STZ, in the sporadic STZ-induced AD model, corresponding to the pre-amyloid and amyloid phases, respectively. Results: We observed a reduction in GS activity and increased MAO-B content, both in 4 weeks and in 16 weeks, reinforcing the idea that astroglial dysfunction precedes the amyloid phase. These alterations were accompanied by an increase in the content of ornithine decarboxylase 1 (ODC1), which catalyzes the synthesis of putrescine (substrate for GABA synthesis, via MAO-B), and a reduction in the gene expression of arginine-glycine amidinotransferase (AGAT), an enzyme involved in the synthesis of creatine, and in the generation of GABA agonists. These changes were only seen in the amyloid phase of the AD model. Conclusions: Our findings contribute to explain the greater damage that occurs in energy metabolism at this stage, in addition to the greater GABAergic loss. The changes reinforce the importance of the STZ model and further our understanding of the changes in both AD phases.

S100B is a calcium-binding protein produced and secreted by astrocytes in response to various extracellular stimuli. C6 glioma cells are a lineage commonly employed for astroglial studies due to the expression of astrocyte specific markers and behavior. However, in high-glucose medium, C6 S100B secretion increases, in contrast to the trend in primary astrocyte cultures. Additionally, S100B secretion decreases due to fluorocitrate (FC), a Krebs cycle inhibitor, highlighting a connection between S100B and metabolism. Herein, we investigate the impact of FC on S100B secretion in primary astrocyte cultures, acute hippocampal slices and C6 glioma cells, as well as lactate mediation. Our results demonstrated that C6 responded similarly to astrocytes in various parameters, despite the decrease in S100B secretion, which was inversely observed in astrocytes and slices. Furthermore, FC inversely altered extracellular lactate in both models, suggesting a role for lactate in S100B secretion. This was reinforced by a decrease in S100B secretion in hippocampal slices treated with lactate and its agonist, but not in C6 cells, despite HCAR1 expression. Our findings indicate that extracellular lactate mediates the decrease in S100B secretion in astrocytes exposed to FC. They also emphasize the differences in C6 glioma cells regarding energetic metabolism. The proposed mechanism via HCAR1 provides further compelling evidence of the relationship between S100B and glucose metabolism.

Background: Advanced glycation end products (AGEs) and receptors for AGEs (RAGE) have been extensively implicated in metabolic and neurodegenerative disorders due to their capacity to alter protein structure and function through non-enzymatic glycation. More recently, methylglyoxal (MG), a highly reactive glycolytic byproduct, has gained attention as a critical mediator of AGE formation and an independent contributor to cellular distress, particularly in the context of diabetes mellitus and Alzheimer’s disease. Objectives: This review synthesizes evidence from experimental and clinical studies addressing MG generation and metabolism in brain tissue, emphasizing the glyoxalase system as the primary detoxification mechanism, the functional contribution of astrocytes, and the downstream consequences of MG accumulation. In addition, we examined the interplay between MG, RAGE signaling, unfolded protein response, and regulatory mechanisms involving the hexosamine biosynthesis pathway and O-GlcNAcylation of key proteins in glucose metabolism and insulin signaling. Results and Conclusions: Brain glucose hypometabolism is a consequence of insulin resistance and results in a metabolic rearrangement that expands the glycolytic pathway and generates more MG, which, in turn, can affect insulin signaling, further compromising the molecular basis of insulin resistance and creating a vicious cycle. Astrocytes are key cells in the generation and detoxification of MG in the brain, making them a therapeutic target.

Background: Elevated levels of methylmalonic acid (MMA) are observed in the bodily fluids and tissues of patients with methylmalonic aciduria, a metabolic disorder characterized by manifestations such as vomiting, lethargy, muscle weakness, seizures, and coma. Objectives and Methods: To better understand the neuropathological mechanisms underlying this condition, we investigated the effects of intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of MMA on antioxidant defenses, citric acid cycle functioning, and glial reactivity in the cerebral cortex and striatum of Wistar rats. Amino acid levels were also quantified. Results: i.p. and i.c.v. administration of MMA decreased reduced glutathione levels and altered the activities of different antioxidant enzymes in the cortex and striatum. The activity of the citric acid cycle enzyme succinate dehydrogenase was diminished in both brain regions by i.p. and i.c.v. administration. Citrate synthase, isocitrate dehydrogenase, and malate dehydrogenase activities were further inhibited in the striatum. Furthermore, the i.p. administration increased glial fibrillary acidic protein (GFAP) and glucose transporter 1 (GLUT1) levels, whereas i.c.v. administration elevated GFAP and ionized calcium-binding adaptor molecule 1 (IBA1) levels in the striatum, suggesting glial activation. In contrast, no significant changes in glial markers were detected in the cortex. Moreover, synaptophysin levels remained unaltered in both regions. Finally, i.p. administration increased glutamate, glycine, and serine levels and reduced tyrosine concentrations in the striatum. Conclusions: Our findings indicate that oxidative stress, bioenergetic dysfunction, and glial reactivity induced by MMA may contribute to the neurological deficits observed in methylmalonic aciduria.

Alzheimer’s disease (AD) is the most prevalent form of dementia, with aging as its primary risk factor. Among experimental models of sporadic AD, intracerebroventricular (ICV) administration of streptozotocin (STZ) in rodents is widely used. We hypothesized that STZ accelerates the process of cellular senescence, which in astrocytes can be assessed using classic markers, including p16, β-galactosidase, Lamin B1, and the senescence-associated secretory phenotype (SASP). To explore this, we cultured hypothalamic astrocytes from adult male Wistar rats at four weeks after STZ-ICV model induction to investigate whether the astroglial changes observed in vivo were maintained under in vitro conditions, and whether markers of senescence were more evident in astrocytes from STZ animals. As in the STZ dementia model, astrocyte cultures exhibited reduced levels of glutamine synthetase and glutathione. Furthermore, elevations in the transcription factors, FOXO3a, Nrf2, and NF-κB, were observed. Markers of unfolded protein response (CHOP and sorcin) were also increased in astrocytes from STZ animals. When evaluating senescence parameters, increases in p53, p21, and p16 were observed, while Lamin B1 levels remained unchanged. With regard to SASP, modulations in TNFα and extracellular HMGB1 and S100B levels also suggested the induction of a senescent profile. Taken together, these findings demonstrate that cultured astrocytes retain key alterations observed in the in vivo model of STZ-induced dementia, highlighting its usefulness for studying AD and therapeutic strategies. Observations in cultures suggest that STZ indeed induces astrocyte senescence and that S100B may be included as a component of the astroglial SASP.