Igor Allaman

Astrocyte-neuron metabolic relationships: for better and for worse

In recent years, previously unsuspected roles of astrocytes have been revealed, largely owing to the development of new tools enabling their selective study in situ. These exciting findings add to the large body of evidence demonstrating that astrocytes play a central role in brain homeostasis, in particular via the numerous cooperative metabolic processes they establish with neurons, such as the supply of energy metabolites and neurotransmitter recycling functions. Furthermore, impairments in astrocytic function are increasingly being recognized as an important contributor to neuronal dysfunction and, in particular, neurodegenerative processes. In this review, we discuss recent evidence supporting important roles for astrocytes in neuropathological conditions such as neuroinflammation, amyotrophic lateral sclerosis and Alzheimers disease. We also explore the potential for neuroprotective therapeutics based on the modulation of astrocytic functions.

A cellular perspective on brain energy metabolism and functional imaging.

The energy demands of the brain are high: they account for at least 20% of the bodys energy consumption. Evolutionary studies indicate that the emergence of higher cognitive functions in humans is associated with an increased glucose utilization and expression of energy metabolism genes. Functional brain imaging techniques such as fMRI and PET, which are widely used in human neuroscience studies, detect signals that monitor energy delivery and use in register with neuronal activity. Recent technological advances in metabolic studies with cellular resolution have afforded decisive insights into the understanding of the cellular and molecular bases of the coupling between neuronal activity and energy metabolism and point at a key role of neuron-astrocyte metabolic interactions. This article reviews some of the most salient features emerging from recent studies and aims at providing an integration of brain energy metabolism across resolution scales.

Amyloid-β Aggregates Cause Alterations of Astrocytic Metabolic Phenotype: Impact on Neuronal Viability

Amyloid-β (Aβ) peptides play a key role in the pathogenesis of Alzheimers disease and exert various toxic effects on neurons; however, relatively little is known about their influence on glial cells. Astrocytes play a pivotal role in brain homeostasis, contributing to the regulation of local energy metabolism and oxidative stress defense, two aspects of importance for neuronal viability and function. In the present study, we explored the effects of Aβ peptides on glucose metabolism in cultured astrocytes. Following Aβ25-35 exposure, we observed an increase in glucose uptake and its various metabolic fates, i.e., glycolysis (coupled to lactate release), tricarboxylic acid cycle, pentose phosphate pathway, and incorporation into glycogen. Aβ increased hydrogen peroxide production as well as glutathione release into the extracellular space without affecting intracellular glutathione content. A causal link between the effects of Aβ on glucose metabolism and its aggregation and internalization into astrocytes through binding to members of the class A scavenger receptor family could be demonstrated. Using astrocyte-neuron cocultures, we observed that the overall modifications of astrocyte metabolism induced by Aβ impair neuronal viability. The effects of the Aβ25-35 fragment were reproduced by Aβ1-42 but not by Aβ1-40. Finally, the phosphoinositide 3-kinase (PI3-kinase) pathway appears to be crucial in these events since both the changes in glucose utilization and the decrease in neuronal viability are prevented by LY294002, a PI3-kinase inhibitor. This set of observations indicates that Aβ aggregation and internalization into astrocytes profoundly alter their metabolic phenotype with deleterious consequences for neuronal viability.

Pro‐inflammatory cytokines induce the transcription factors C/EBPβ and C/EBPδ in astrocytes

The transcription factors CCAAT/enhancer binding protein (C/EBP)‐β and ‐δ are key regulators for the expression of the acute phase genes in the liver, such as complement component C3 and antichymotrypsin. In the brain, these acute phase proteins are produced in response to pro‐inflammatory cytokines by the reactive astrocytes, in particular those surrounding the amyloid plaques of Alzheimers disease brains. Here we show that lipopolysaccharides (LPS), IL‐1β, and TNFα induce the expression of the c/ebpβ and ‐δ genes in mouse primary astrocytes. This induction precedes the expression of the acute phase genes coding for the complement component C3 and the mouse homologue of antichymotrypsin. The induction of these two acute phase genes by LPS is blocked by cycloheximide, whereas this protein synthesis inhibitor does not affect the expression of the c/ebp genes. Altogether, our data support a role as immediate‐early genes for c/ebpβ and ‐δ, whose expression is induced by pro‐inflammatory cytokines in mouse cortical astrocytes. In the liver, these transcription factors are known to play an important role in inflammation and energy metabolism regulation. Therefore, C/EBPβ and ‐δ could be pivotal transcription factors involved in brain inflammation, in addition to their previously demonstrated role in brain glycogen metabolism regulation (Cardinaux and Magistretti. J Neurosci 16:919–929, 1996). GLIA 29:91–97, 2000.

Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

Significance The transfer of lactate, a product of aerobic glycolysis, from astrocytes to neurons was recently shown to be necessary for the establishment of long-term memory and for the maintenance of in vivo long-term potentiation. Here, we report that lactate induces the expression of plasticity genes such as Arc, c-Fos, and Zif268 in neurons. The action of lactate is mediated by the modulation of NMDA receptor activity and the downstream Erk1/2 signaling cascade, through a mechanism associated with changes in the cellular redox state. These observations unveil an unexpected role of lactate as a signaling molecule in addition to its role in energy metabolism and open a previously unidentified research avenue for the study of neuronal plasticity and memory. l-lactate is a product of aerobic glycolysis that can be used by neurons as an energy substrate. Here we report that in neurons l-lactate stimulates the expression of synaptic plasticity-related genes such as Arc, c-Fos, and Zif268 through a mechanism involving NMDA receptor activity and its downstream signaling cascade Erk1/2. l-lactate potentiates NMDA receptor-mediated currents and the ensuing increase in intracellular calcium. In parallel to this, l-lactate increases intracellular levels of NADH, thereby modulating the redox state of neurons. NADH mimics all of the effects of l-lactate on NMDA signaling, pointing to NADH increase as a primary mediator of l-lactate effects. The induction of plasticity genes is observed both in mouse primary neurons in culture and in vivo in the mouse sensory-motor cortex. These results provide insights for the understanding of the molecular mechanisms underlying the critical role of astrocyte-derived l-lactate in long-term memory and long-term potentiation in vivo. This set of data reveals a previously unidentified action of l-lactate as a signaling molecule for neuronal plasticity.

Aβ42 Neurotoxicity Is Mediated by Ongoing Nucleated Polymerization Process Rather than by Discrete Aβ42 Species

The identification of toxic Aβ species and/or the process of their formation is crucial for understanding the mechanism(s) of Aβ neurotoxicity in Alzheimer disease and also for the development of effective diagnostic and therapeutic interventions. To elucidate the structural basis of Aβ toxicity, we developed different procedures to isolate Aβ species of defined size and morphology distribution, and we investigated their toxicity in different cell lines and primary neurons. We observed that crude Aβ42 preparations, containing a monomeric and heterogeneous mixture of Aβ42 oligomers, were more toxic than purified monomeric, protofibrillar fractions, or fibrils. The toxicity of protofibrils was directly linked to their interactions with monomeric Aβ42 and strongly dependent on their ability to convert into amyloid fibrils. Subfractionation of protofibrils diminished their fibrillization and toxicity, whereas reintroduction of monomeric Aβ42 into purified protofibril fractions restored amyloid formation and enhanced their toxicity. Selective removal of monomeric Aβ42 from these preparations, using insulin-degrading enzyme, reversed the toxicity of Aβ42 protofibrils. Together, our findings demonstrate that Aβ42 toxicity is not linked to specific prefibrillar aggregate(s) but rather to the ability of these species to grow and undergo fibril formation, which depends on the presence of monomeric Aβ42. These findings contribute significantly to the understanding of amyloid formation and toxicity in Alzheimer disease, provide novel insight into mechanisms of Aβ protofibril toxicity, and important implications for designing anti-amyloid therapies.

Brain Energy Metabolism

All the cellular processes supporting brain functions require energy. Careful consideration of brain energy metabolism is an essential prerequisite to a full understanding of the physiology and pathophysiology of brain functions. One of the main features of brain energy metabolism is its dependence on glucose metabolism. Brain energy metabolism is characterized by a complex interplay between different neural cell types. In this chapter the features of brain energy metabolism are reviewed at the global, regional, and cellular levels. Recent advances in the understanding of neuro-glial metabolic cooperation are extensively reviewed. A particular focus has been placed on the cellular and molecular mechanisms that tightly couple neuronal activity to energy consumption—a process that is at the basis of functional brain-imaging techniques, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI).

Fluoxetine regulates the expression of neurotrophic/growth factors and glucose metabolism in astrocytes

RationaleThe pharmacological actions of most antidepressants are ascribed to the modulation of serotonergic and/or noradrenergic transmission in the brain. During therapeutic treatment for major depression, fluoxetine, one of the most commonly prescribed selective serotonin reuptake inhibitor (SSRI) antidepressants, accumulates in the brain, suggesting that fluoxetine may interact with additional targets. In this context, there is increasing evidence that astrocytes are involved in the pathophysiology of major depression.ObjectivesThe aim of this study was to examine the effects of fluoxetine on the expression of neurotrophic/growth factors that have antidepressant properties and on glucose metabolism in cultured cortical astrocytes.ResultsTreatment of astrocytes with fluoxetine and paroxetine, another SSRI antidepressant, upregulated brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and VGF mRNA expression. In contrast, the tricyclic antidepressants desipramine and imipramine did not affect the expression of these neurotrophic/growth factors. Analysis of the effects of fluoxetine on glucose metabolism revealed that fluoxetine reduces glycogen levels and increases glucose utilization and lactate release by astrocytes. Similar data were obtained with paroxetine, whereas imipramine and desipramine did not regulate glucose metabolism in this glial cell population. Our results also indicate that the effects of fluoxetine and paroxetine on glucose utilization, lactate release, and expression of BDNF, VEGF, and VGF are not mediated by serotonin-dependent mechanisms.ConclusionsThese data suggest that, by increasing the expression of specific astrocyte-derived neurotrophic factors and lactate release from astrocytes, fluoxetine may contribute to normalize the trophic and metabolic support to neurons in major depression.

Methylglyoxal, the dark side of glycolysis

Glucose is the main energy substrate for the brain. There is now extensive evidence indicating that the metabolic profile of neural cells with regard to glucose utilization and glycolysis rate is not homogenous, with a marked propensity for glycolytic glucose processing in astrocytes compared to neurons. Methylglyoxal, a highly reactive dicarbonyl compound, is inevitably formed as a by-product of glycolysis. Methylglyoxal is a major cell-permeant precursor of advanced glycation end-products (AGEs), which are associated with several pathologies including diabetes, aging and neurodegenerative diseases. In normal situations, cells are protected against methylglyoxal toxicity by different mechanisms and in particular the glyoxalase system, which represents the most important pathway for the detoxification of methylglyoxal. While the neurotoxic effects of methylglyoxal and AGEs are well characterized, our understanding the glyoxalase system in the brain is more scattered. Considering the high energy requirements (i.e., glucose) of the brain, one should expect that the cerebral glyoxalase system is adequately fitted to handle methylglyoxal toxicity. This review focuses on our actual knowledge on the cellular aspects of the glyoxalase system in brain cells, in particular with regard to its activity in astrocytes and neurons. A main emerging concept is that these two neural cell types have different and energetically adapted glyoxalase defense mechanisms which may serve as protective mechanism against methylglyoxal-induced cellular damage.

Olfaction in birds: differential embryonic expression of nine putative odorant receptor genes in the avian olfactory system

We have isolated nine putative odorant receptor genes from the chick, named COR1 to COR9, that belong to the large multigene family of olfactory G protein-coupled receptors found in the fish, rat, mouse, dog, and human. By combining genomic DNA blot analysis, low stringency library screenings, and several PCR analyses, we were able to detect approximately 20 COR genes in the chick genome highly related to COR1-9. By in situ hybridization of newborn and adult, COR expression was detected only in the olfactory epithelium, and exhibited a random spatial distribution. During development, COR expression was observed as early as embryonic stage E5. Different levels of gene expression were observed for the COR1-9 genes: at E5, COR1-6 expression was high compared to the expression of COR7, COR8, and COR9. Surprisingly, at E5, a row of COR1-6 positive cells probably associated with the olfactory nerve extended outside the olfactory placode, reaching the anterior pole of the developing forebrain. These results suggest that, in addition to their role as putative odorant receptors, some COR may play a role in the development of the avian olfactory system.