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Brain lactate shuttle. Astrocytes convert glucose and glycogen into lactate, which is exported via monocarboxylate transporters MCTs and ion channels. Neurons import glucose and lactate for mitochondrial oxidation
Source publication
Glycolysis is the core of intermediate metabolism, an ancient pathway discovered in the heydays of classic biochemistry. A hundred years later, it remains a matter of active research, clinical interest and is not devoid of controversy. This review examines topical aspects of glycolysis in the brain, a tissue characterized by an extreme dependence o...
Citations
... As reported by Bergau et al. [10], patients with AD displayed a reduction of glycolytic flux in the cerebrospinal fluid, and the reduction of glycolytic flux was correlated with the severity of Ab and tau pathology [11]. Furthermore, significant changes in the activity and protein levels of cerebral glycolytic key enzymes including hexokinase (HK), phosphofructokinase M1 isoform (PFKM1), and pyruvate kinase M1 isoform (PKM1) have been demonstrated in the brains of patients with AD and rodent models of AD [12][13][14][15]. Therefore, improving glycolytic dysfunction may be an important strategy for treating AD by regulating the activities of key glycolysis enzymes. ...
... Recent extensive evidence has shown that in patients with AD and rodent models with AD, significant changes have taken place in the activity and protein expression levels of key glycolytic enzymes (including HK, PFKM1and PKM1) in the brain [14,15]. Expression of HK is reduced in AD transgenic mice and brain tissue from patients with AD [51]. ...
It was reported that the Wnt/β‐catenin pathway is involved in the regulation of aerobic glycolysis and that brain glycolytic dysfunction results in the development of Alzheimer's disease (AD). Icariin (ICA), an active component extracted from Epimedii Folium, has been reported to produce neuroprotective effects in multiple models of AD, but its underlying mechanism remains to be fully described. We aimed to investigate the protective effects of ICA on animal and cell models of AD and confirm whether the Wnt/β‐catenin pathway has functions in the neuroprotective function of ICA. The 3 × Tg‐AD mice were treated with ICA. HT22 cells, the Aβ25‐35 peptide and Dickkopf‐1 (DKK1) agent (a specific inhibitor of the Wnt/β‐catenin pathway) were used to further explore the underlying mechanism of ICA that produces anti‐AD effects. Behavioral examination, western blotting assay, staining analysis, biochemical test, and lactate dehydrogenase (LDH) assays were applied. We first demonstrated that ICA significantly improved cognitive function and autonomous behavior, reduced neuronal damage, and reversed the protein levels and activities of glycolytic key enzymes, and expression of protein molecules of the canonical Wnt signaling pathway, in 3 × Tg‐AD mice back to wild‐type levels. Next, we further found that ICA increased cell viability and effectively improved the dysfunctional glycolysis in HT22 cells injured by Aβ25‐35. However, when canonical Wnt signaling was inhibited by DKK1, the above effects of ICA on glycolysis were abolished. In summary, ICA exerts neuroprotective effects in 3 × Tg‐AD animals and AD cellular models by enhancing the function of glycolysis through activation of the Wnt/β‐catenin pathway.
... Lactate is proposed to be the end-product of glycolysis in brain tissue where the cytosolic levels of lactate are at least 10 times higher than that of pyruvate, due to the high affinity of LDH for pyruvate and mitochondrial pyruvate consumption. [2][3][4][5][6] Over the past two decades, the concept of lactate as an energetic substrate in the brain has attracted attention. The seminal work of Pellerin and Magistretti showed that glutamate uptake stimulates aerobic glycolysis in astrocytes and leads to the release of lactate. ...
Under physiological conditions, the energetic demand of the brain is met by glucose oxidation. However, ample evidence suggests that lactate produced by astrocytes through aerobic glycolysis may also be an oxidative fuel, highlighting the metabolic compartmentalization between neural cells. Herein, we investigate the roles of glucose and lactate in oxidative metabolism in hippocampal slices, a model that preserves neuron-glia interactions. To this purpose, we used high-resolution respirometry to measure oxygen consumption (O2 flux) at the whole tissue level and amperometric lactate microbiosensors to evaluate the concentration dynamics of extracellular lactate. We found that lactate is produced from glucose and transported to the extracellular space by neural cells in hippocampal tissue. Under resting conditions, endogenous lactate was used by neurons to support oxidative metabolism, which was boosted by exogenously added lactate even in the presence of excess glucose. Depolarization of hippocampal tissue with high K+ significantly increased the rate of oxidative phosphorylation, which was accompanied by a transient decrease in extracellular lactate concentration. Both effects were reverted by inhibition of the neuronal lactate transporter, monocarboxylate transporters 2 (MCT2), supporting the concept of an inward flux of lactate to neurons to fuel oxidative metabolism. We conclude that astrocytes are the main source of extracellular lactate which is used by neurons to fuel oxidative metabolism, both under resting and stimulated conditions.
... The major cellular energy pathways include glycolysis, citric acid cycle followed by oxidative phosphorylation (OXPHOS) and fatty acid β oxidation [7][8][9]. Because of their anatomical position, between capillaries and neurons, astrocytes constitute an interface for effective glucose uptake from the blood. ...
... It has been shown that Aβ induces energy production in microglia to shift from OXPHOS to glycolysis [42], therefore we investigated if this was also the case in the astrocytic cultures. Astrocytes are glycolytic cells that have lactate as an end-product of glycolysis instead of pyruvate [7]. We analyzed the levels of LDH, the enzyme that converts pyruvate into lactate, and lactate in order to investigate if the energy production had switched to glycolysis. ...
Background
Astrocytes play a central role in maintaining brain energy metabolism, but are also tightly connected to the pathogenesis of Alzheimer’s disease (AD). Our previous studies demonstrate that inflammatory astrocytes accumulate large amounts of aggregated amyloid-beta (Aβ). However, in which way these Aβ deposits influence their energy production remain unclear.
Methods
The aim of the present study was to investigate how Aβ pathology in astrocytes affects their mitochondria functionality and overall energy metabolism. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated Aβ42 fibrils for 7 days and analyzed over time using different experimental approaches.
Results
Our results show that to maintain stable energy production, the astrocytes initially increased their mitochondrial fusion, but eventually the Aβ-mediated stress led to abnormal mitochondrial swelling and excessive fission. Moreover, we detected increased levels of phosphorylated DRP-1 in the Aβ-exposed astrocytes, which co-localized with lipid droplets. Analysis of ATP levels, when blocking certain stages of the energy pathways, indicated a metabolic shift to peroxisomal-based fatty acid β-oxidation and glycolysis.
Conclusions
Taken together, our data conclude that Aβ pathology profoundly affects human astrocytes and changes their entire energy metabolism, which could result in disturbed brain homeostasis and aggravated disease progression.
... Наиболее уязвимыми в условиях гипоксии оказываются нервные клетки центральной нервной системы, поскольку их энергопотребление исключительно высоко, а запасы дыхательных субстратов в виде гликогена (как, например, в мышцах) крайне ограничены или отсутствуют. Кроме того, при гипоксии нейроны мозга, в отличие от клеток периферических тканей, не могут долго получать энергию за счет запуска процессов гликолиза [2]. В связи с этим при обсуждении механизмов гипоксического клеточного патогенеза и путей защиты от него имеют в виду в первую очередь нейроны головного мозга. ...
02.09.2022 г. После доработки 07.11.2022 г. Принята к публикации 07.11.2022 г.
В настоящее время наблюдается новый всплеск интереса к проблеме гипоксии, почти утраченный в последние десятилетия. В связи с тем, что когорта компетентных специалистов в этой области существенно сократилась, необходимо осуществлять интенсивный обмен знаниями. С целью проинформировать широкий круг заинтересованных исследователей и врачей, в настоящем обзоре обобщено современное понимание гипоксии, ее патогенных и адаптогенных последствий, а также ключевых физиологических и молекулярных механизмов, которые реализуют реакцию на гипоксию на различных уровнях-от клеточного до организменного. В обзоре приведена современная классификация форм гипоксии, понимание которой необходимо для формирования научно обоснованного подхода к экспериментальному моделированию гипоксических состояний. Про-веден анализ литературы, освещающий историю и современный уровень моделирования гипоксии в экспериментах на млекопитающих животных и человеке, в том числе способов создания умеренной гипоксии, применяемой для повыше-ния резистентности нервной системы к тяжелым формам гипоксии и другим экстремальным факторам. Отдельное внимание уделяется обсуждению особенностей и ограничений различных подходов к созданию гипоксии, а также раскрытию потенциала практического применения умеренных гипоксических воздействий в лечебной и профилактической медицине. Ключевые слова: гипоксия, классификация форм, экспериментальные модели гипоксии/ишемии, гипоксическая толерантность, мозг
... The most vulnerable in hypoxia are nerve cells of the central nervous sys tem, because their energy consumption is extremely high, and the reserves of respiratory substrates in the form of glycogen (such as in mus cles) are extremely limited or absent. Moreover, under hypoxia, brain neurons, unlike the cells of peripheral tissues, cannot get energy by triggering glycolysis processes for a long time [2]. Therefore, when discussing the mechanisms of hypoxic cel lular pathogenesis and the ways to protect against it, brain neurons are primarily meant. ...
Currently, there is a new surge of interest in the problem of hypoxia, almost lost in recent decades. Due to the fact that the circle of competent specialists in this field has significantly narrowed, it is necessary to carry out an intensive exchange of knowledge. In order to inform a wide range of interested researchers and doctors, this review summarizes the current understanding of hypoxia, its pathogenic and adaptogenic consequences, as well as key physiological and molecular mechanisms that implement the response to hypoxia at various levels-from cellular to organismic. The review presents a modern classification of forms of hypoxia, the understanding of which is necessary for the formation of a scientifically based approach to experimental modeling of hypoxic states. An analysis of the literature covering the history and current level of hypoxia modeling in mammals and human experiments, including methods for creating moderate hypoxia used to increase the resistance of the nervous system to severe forms of hypoxia and other extreme factors, is carried out. Special attention is paid to the discussion of the features and limitations of various approaches to the creation of hypoxia, as well as the disclosure of the potential for the practical application of moderate hypoxic effects in medicine.
... However, in astrocytes exposed to elevated [K + ] e , ATP levels actually rise (80,88), which means that adenine nucleotides are not the signal between the astrocytic NKA and K + -stimulated glycolysis. This nagging knowledge gap between the transduction of extracellular signals at the cell surface and the metabolic machinery is also present in neurons (1,89). In addition to NKA α2β2 engagement, the stimulation of astrocytic glycolysis by [K + ] e requires coactivation of the NBCe1, as demonstrated in culture and tissue slices by functional, pharmacological, and genetic means (57, 79) (Figure 3d). ...
Information processing imposes urgent metabolic demands on neurons, which have negligible energy stores and restricted access to fuel. Here, we discuss metabolic recruitment, the tissue-level phenomenon whereby active neurons harvest resources from their surroundings. The primary event is the neuronal release of K ⁺ that mirrors workload. Astrocytes sense K ⁺ in exquisite fashion thanks to their unique coexpression of NBCe1 and α2β2 Na ⁺ [Formula: see text]K ⁺ ATPase, and within seconds switch to Crabtree metabolism, involving GLUT1, aerobic glycolysis, transient suppression of mitochondrial respiration, and lactate export. The lactate surge serves as a secondary recruiter by inhibiting glucose consumption in distant cells. Additional recruiters are glutamate, nitric oxide, and ammonium, which signal over different spatiotemporal domains. The net outcome of these events is that more glucose, lactate, and oxygen are made available. Metabolic recruitment works alongside neurovascular coupling and various averaging strategies to support the inordinate dynamic range of individual neurons.
Expected final online publication date for the Annual Review of Physiology, Volume 85 is February 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... As can be observed in Figure 5B, incremental changes in lactate increased the current measured by the lactate sensor, while the current from the sentinel sensor remained unchanged. This control experiment was performed in the absence of glucose to discard the contribution of endogenous lactate [40][41][42]. ...
Background:
Direct and real-time monitoring of lactate in the extracellular space can help elucidate the metabolic and modulatory role of lactate in the brain. Compared to in vivo studies, brain slices allow the investigation of the neural contribution separately from the effects of cerebrovascular response and permit easy control of recording conditions.
Methods:
We have used a platinized carbon fiber microelectrode platform to design an oxidase-based microbiosensor for monitoring lactate in brain slices with high spatial and temporal resolution operating at 32 °C. Lactate oxidase (Aerococcus viridans) was immobilized by crosslinking with glutaraldehyde and a layer of polyurethane was added to extend the linear range. Selectivity was improved by electropolymerization of m-phenylenediamine and concurrent use of a null sensor.
Results:
The lactate microbiosensor exhibited high sensitivity, selectivity, and optimal analytical performance at a pH and temperature compatible with recording in hippocampal slices. Evaluation of operational stability under conditions of repeated use supports the suitability of this design for up to three repeated assays.
Conclusions:
The microbiosensor displayed good analytical performance to monitor rapid changes in lactate concentration in the hippocampal tissue in response to potassium-evoked depolarization.
... The brain represents 2% of the body mass in adults, yet the energy demands to maintain adequate brain function require 20-25% of total body glucose utilisation and~20% of the oxygen consumption [95,96]. In the adult brain, glucose is the obligate energy substrate for the production of adenosine triphosphate (ATP), except under particular circumstances where ketone bodies (e.g., during fasting) and lactate (e.g., during intense physical activity) are also utilised [97,98]. Circulating glucose enters the brain parenchyma by facilitated transport via 55-kDa glucose transporter 1 (GLUT1) on the capillary endothelial cells, and is subsequently taken up by neurons (via GLUT3) and glial cells [95,99,100]. ...
... However, another study showed that liraglutide inhibited glucose uptake in cultured astrocytes, while promoting β-oxidation of fatty acids for ATP generation [220]. Further related to the glucose metabolism, another feature that is peculiar to astroglial cells (although not exclusive) is the glycogen storage, which can be mobilised in the events of increased energy demand and during brain repair [97,221]. The evidence for this is based on the observations that glycogen levels in the brain are increased when neuronal activity is inhibited (e.g., under general anaesthesia) [227]. ...
Defects in brain energy metabolism and proteopathic stress are implicated in age-related degenerative neuronopathies, exemplified by Alzheimer’s disease (AD) and Parkinson’s disease (PD). As the currently available drug regimens largely aim to mitigate cognitive decline and/or motor symptoms, there is a dire need for mechanism-based therapies that can be used to improve neuronal function and potentially slow down the underlying disease processes. In this context, a new class of pharmacological agents that achieve improved glycaemic control via the glucagon-like peptide 1 (GLP-1) receptor has attracted significant attention as putative neuroprotective agents. The experimental evidence supporting their potential therapeutic value, mainly derived from cellular and animal models of AD and PD, has been discussed in several research reports and review opinions recently. In this review article, we discuss the pathological relevance of derangements in the neurovascular unit and the significance of neuron–glia metabolic coupling in AD and PD. With this context, we also discuss some unresolved questions with regard to the potential benefits of GLP-1 agonists on the neurovascular unit (NVU), and provide examples of novel experimental paradigms that could be useful in improving our understanding regarding the neuroprotective mode of action associated with these agents.
... Lactate is a metabolic end-product that cannot directly be used and requires its conversion into pyruvate to serve as energy and carbon source to the tricarboxylic acid (TCA) cycle (Barros et al., 2020). One of the advantages of producing lactate that is not readily consumed is to allow its distribution and exchanges between lactate producing and lactate consuming cells (Brooks, 2018). ...
Astrocytes play key roles in the regulation of brain energy metabolism, which has a major impact on brain functions, including memory, neuroprotection, resistance to oxidative stress and homeostatic tone. Energy demands of the brain are very large, as they continuously account for 20–25% of the whole body’s energy consumption. Energy supply of the brain is tightly linked to neuronal activity, providing the origin of the signals detected by the widely used functional brain imaging techniques such as functional magnetic resonance imaging and positron emission tomography. In particular, neuroenergetic coupling is regulated by astrocytes through glutamate uptake that triggers astrocytic aerobic glycolysis and leads to glucose uptake and lactate release, a mechanism known as the Astrocyte Neuron Lactate Shuttle. Other neurotransmitters such as noradrenaline and Vasoactive Intestinal Peptide mobilize glycogen, the reserve for glucose exclusively localized in astrocytes, also resulting in lactate release. Lactate is then transferred to neurons where it is used, after conversion to pyruvate, as a rapid energy substrate, and also as a signal that modulates neuronal excitability, homeostasis, and the expression of survival and plasticity genes. Importantly, glycolysis in astrocytes and more generally cerebral glucose metabolism progressively deteriorate in aging and age-associated neurodegenerative diseases such as Alzheimer’s disease. This decreased glycolysis actually represents a common feature of several neurological pathologies. Here, we review the critical role of astrocytes in the regulation of brain energy metabolism, and how dysregulation of astrocyte-mediated metabolic pathways is involved in brain hypometabolism. Further, we summarize recent efforts at preclinical and clinical stages to target brain hypometabolism for the development of new therapeutic interventions in age-related neurodegenerative diseases.
... After phosphorylation, G6P may form glycogen or enter the PPP (Figure 2). In addition, glycolysis is branching off and on at multiple points, likely suggesting that pyruvate is not made at the same rate that glucose is consumed, as elegantly reminded by Felipe Barros (Barros et al., 2020). As we already mentioned above, glycolytic intermediates are providing carbons to generate biomass (Lunt and Vander Heiden, 2011). ...
The brain has almost no energy reserve, but its activity coordinates organismal function, a burden that requires precise coupling between neurotransmission and energy metabolism. Deciphering how the brain accomplishes this complex task is crucial to understand central facets of human physiology and disease mechanisms. Each type of neural cell displays a peculiar metabolic signature, forcing the intercellular exchange of metabolites that serve as both energy precursors and paracrine signals. The paradigm of this biological feature is the astrocyte-neuron couple, in which the glycolytic metabolism of astrocytes contrasts with the mitochondrial oxidative activity of neurons. Astrocytes generate abundant mitochondrial reactive oxygen species and shuttle to neurons glycolytically derived metabolites, such as L-lactate and L-serine, which sustain energy needs, conserve redox status, and modulate neurotransmitter-receptor activity. Conversely, early disruption of this metabolic cooperation may contribute to the initiation or progression of several neurological diseases, thus requiring innovative therapies to preserve brain energetics.
