Astrocyte energy and neurotransmitter metabolism in Alzheimer’s disease: Integration of the glutamate/GABA-glutamine cycle

Progress in Neurobiology, Год журнала: 2022, Номер 217, С. 102331 - 102331

Опубликована: Июль 21, 2022

Язык: Английский

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Glutamate excitotoxicity: Potential therapeutic target for ischemic stroke

Biomedicine & Pharmacotherapy, Год журнала: 2022, Номер 151, С. 113125 - 113125

Опубликована: Май 24, 2022

Glutamate-mediated excitotoxicity is an important mechanism leading to post ischemic stroke damage. After acute stroke, the sudden reduction in cerebral blood flow most initially followed by ion transport protein dysfunction and disruption of homeostasis, which turn leads impaired glutamate release, reuptake, excessive N-methyl-D-aspartate receptor (NMDAR) activation, promoting neuronal death. Despite extensive evidence from preclinical studies suggesting that NMDAR stimulation during a central step post-stroke damage, blockers have failed translate into clinical treatment. Current treatment options for are very limited, there therefore great need develop new targets neuroprotective therapeutic agents extend time window. In this review, we highlight recent findings on reuptake mechanisms, its downstream cellular signaling pathways post-ischemic review pathological changes each link help viable targets. We then also summarize potential drugs approaches these stroke.

Язык: Английский

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Investigating Casual Associations Among Gut Microbiota, Metabolites, and Neurodegenerative Diseases: A Mendelian Randomization Study

Journal of Alzheimer s Disease, Год журнала: 2022, Номер 87(1), С. 211 - 222

Опубликована: Март 8, 2022

Recent studies had explored that gut microbiota was associated with neurodegenerative diseases (including Alzheimer's disease (AD), Parkinson's (PD), and amyotrophic lateral sclerosis (ALS)) through the gut-brain axis, among which metabolic pathways played an important role. However, underlying causality remained unclear.Our study aimed to evaluate potential causal relationships between microbiota, metabolites, Mendelian randomization (MR) approach.We selected genetic variants traits (N = 18,340) microbiota-derived metabolites 7,824) from genome-wide association studies. Summary statistics of were obtained IGAP (AD, 17,008 cases; 37,154 controls), IPDGC (PD, 37,688 141,779 IALSC (ALS, 20,806 59,804 controls) respectively.Greater abundance Ruminococcus (OR, 1.245; 95% CI, 1.103-1.405; p 0.0004) found significantly related higher risk ALS. Besides, our suggestive associations Actinobacteria, Lactobacillaceae, Faecalibacterium, Ruminiclostridium, Lachnoclostridium AD, Lentisphaerae, Lentisphaeria, Oxalobacteraceae, Victivallales, Bacillales, Eubacteriumhalliigroup, Anaerostipes, Clostridiumsensustricto1 PD, Lachnospira, Fusicatenibacter, Catenibacterium, Ruminococcusgnavusgroup Our also revealed 12 microbiome-dependent diseases. Glutamine lower AD. For serotonin pathway, as a protective factor while kynurenine for ALS.Our firstly applied two-sample MR approach detect findings may provide new targets treatments offer valuable insights further on mechanisms.

Язык: Английский

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Milestone Review: Metabolic dynamics of glutamate and GABA mediated neurotransmission — The essential roles of astrocytes

Journal of Neurochemistry, Год журнала: 2023, Номер 166(2), С. 109 - 137

Опубликована: Март 15, 2023

Abstract Since it was first generally accepted that the two amino acids glutamate and GABA act as principal neurotransmitters, several landmark discoveries relating to this function have been uncovered. Synaptic homeostasis of these transmitters involves cell types working in close collaboration is facilitated by specialized cellular processes. Notably, are extensively recycled between neurons astrocytes a process known glutamate/GABA‐glutamine cycle, which essential maintain synaptic transmission. The cycle intimately coupled energy metabolism relies on metabolic both astrocytes. Importantly, display unique features allowing extensive metabolite release, hereby providing support for neurons. Furthermore, undergo complex adaptations response injury pathology, may greatly affect transmission during disease. In Milestone Review we outline major relation balancing signaling, including uptake, metabolism, recycling. We provide special focus how astrocyte contribute sustain neuronal through transfer. Recent advances reviewed context brain toxicity neurodegeneration. Finally, consider pathological serve potential target intervention. Integrating multitude fine‐tuned processes supporting neurotransmitter recycling, will aid next generation homeostasis. image

Язык: Английский

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Neurotransmitters in Prevention and Treatment of Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(4), С. 3841 - 3841

Опубликована: Фев. 14, 2023

Alzheimer’s disease (AD) is the most frequent cause of cognitive impairment in middle-aged and older populations. There a lack drugs that demonstrate significant efficacy AD, so study pathogenesis AD great importance. More efficacious interventions are needed, as reflected by our population’s fast aging. Synaptic plasticity capacity neurons to adjust their connections, it strongly tied learning memory, function, brain injury recovery. Changes synaptic strength, such long-term potentiation (LTP) or inhibition (LTD), thought represent biological foundation early stages memory. The results numerous studies confirm neurotransmitters receptors play an important role regulation plasticity. However, far, there no definite correlation between function aberrant neural oscillation AD-related impairment. We summarized process understand impact progression including current status neurotransmitter target drugs, latest evidence neurotransmitters’ changes process.

Язык: Английский

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Brain energy metabolism: A roadmap for future research

Journal of Neurochemistry, Год журнала: 2024, Номер 168(5), С. 910 - 954

Опубликована: Янв. 6, 2024

Although we have learned much about how the brain fuels its functions over last decades, there remains still to discover in an organ that is so complex. This article lays out major gaps our knowledge of interrelationships between metabolism and function, including biochemical, cellular, subcellular aspects functional imaging adult brain, as well during development, aging, disease. The focus on unknowns substrates associated transporters, roles insulin lipid droplets, emerging role microglia, mysteries cofactor signaling molecule NAD

Язык: Английский

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The role of glutamate and glutamine metabolism and related transporters in nerve cells

CNS Neuroscience & Therapeutics, Год журнала: 2024, Номер 30(2)

Опубликована: Фев. 1, 2024

Glutamate and glutamine are the most abundant amino acids in blood play a crucial role cell survival nervous system. Various transporters found mitochondrial membranes, such as solute carriers (SLCs) superfamily, responsible for maintaining balance of glutamate synaptic cleft within cells. This affects metabolism non-essential acids.

Язык: Английский

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Hippocampal disruptions of synaptic and astrocyte metabolism are primary events of early amyloid pathology in the 5xFAD mouse model of Alzheimer’s disease

Cell Death and Disease, Год журнала: 2021, Номер 12(11)

Опубликована: Окт. 16, 2021

Abstract Alzheimer’s disease (AD) is an unremitting neurodegenerative disorder characterized by cerebral amyloid-β (Aβ) accumulation and gradual decline in cognitive function. Changes brain energy metabolism arise the preclinical phase of AD, suggesting important metabolic component early AD pathology. Neurons astrocytes function close collaboration, which essential for recycling neurotransmitters synapse. However, this crucial interplay during stages development has not been sufficiently investigated. Here, we provide integrative analysis cellular Aβ cortex hippocampus 5xFAD mouse model AD. Our electrophysiological examination revealed increase spontaneous excitatory signaling hippocampus. This hyperactive neuronal phenotype coincided with decreased hippocampal tricarboxylic acid (TCA) cycle mapped stable 13 C isotope tracing. Particularly, reduced astrocyte TCA activity glutamine synthesis led to hampered GABA In contrast, mice displayed elevated capacity oxidative glucose metabolism, may suggest a compensation region. We found limited changes when explored proteome metabolome mice, supporting that functional disturbances between neurons are primary events addition, synaptic mitochondrial glycolytic was selectively impaired hippocampus, whereas non-synaptic maintained. These findings were supported ultrastructural analyses demonstrating disruptions morphology, particularly Collectively, our study reveals complex regional cell-specific adaptations amyloid pathology, be fundamental progressing dysfunctions

Язык: Английский

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Autism Spectrum Disorder: Focus on Glutamatergic Neurotransmission

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(7), С. 3861 - 3861

Опубликована: Март 31, 2022

Disturbances in the glutamatergic system have been increasingly documented several neuropsychiatric disorders, including autism spectrum disorder (ASD). Glutamate-centered theories of ASD are based on evidence from patient samples and postmortem studies, as well studies documenting abnormalities gene expression metabolic pathways, changes gut microbiota glutamate metabolism patients with ASD. In addition, preclinical animal models demonstrated neurotransmission deficits altered synaptic proteins. At present, there no approved drugs for ASD, but ongoing clinical trials currently focusing evaluating autistic pharmaceuticals already other conditions. this review, we provide an overview literature concerning role pathophysiology a potential target novel treatments.

Язык: Английский

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Astrocyte metabolism of the medium-chain fatty acids octanoic acid and decanoic acid promotes GABA synthesis in neurons via elevated glutamine supply

Molecular Brain, Год журнала: 2021, Номер 14(1)

Опубликована: Сен. 3, 2021

Abstract The medium-chain fatty acids octanoic acid (C8) and decanoic (C10) are gaining attention as beneficial brain fuels in several neurological disorders. protective effects of C8 C10 have been proposed to be driven by hepatic production ketone bodies. However, plasma levels correlates poorly with the cerebral C10, suggesting that additional mechanism place. Here we investigated cellular metabolism explored how may linked metabolism. Using dynamic isotope labeling, [U- 13 C]C8 C]C10 metabolic substrates, show both oxidatively metabolized mouse slices. C enrichment from was particularly prominent glutamine, primarily occurs astrocytes. This finding corroborated cultured astrocytes which increased respiration ATP production, whereas elevated mitochondrial proton leak. When were provided together substrates slices, predominant over C8. Furthermore, unaffected etomoxir indicating it is independent carnitine palmitoyltransferase I (CPT-1). Finally, inhibition glutamine synthesis selectively reduced accumulation GABA demonstrating generated astrocyte utilized for neuronal synthesis. Collectively, results coupling neurons astrocytes, serve a supplementation

Язык: Английский

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