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

Progress in Neurobiology, Journal Year: 2022, Volume and Issue: 217, P. 102331 - 102331

Published: July 21, 2022

Language: Английский

---

Brain Energy Metabolism: Astrocytes in Neurodegenerative Diseases

CNS Neuroscience & Therapeutics, Journal Year: 2022, Volume and Issue: 29(1), P. 24 - 36

Published: Oct. 3, 2022

Abstract Astrocytes are the most abundant cells in brain. They have many important functions central nervous system (CNS), including maintenance of glutamate and ion homeostasis, elimination oxidative stress, energy storage glycogen, tissue repair, regulating synaptic activity by releasing neurotransmitters, participating formation. special highly ramified structure. Their branches contact with synapses neurons inwardly, fine structure wrapping synapses; their feet blood vessels brain parenchyma outward, almost whole The adjacent astrocytes rarely overlap communicate each other through gap junction channels. ideal location enables them to sense weak changes surroundings provide structural basis for supply neurons. Neurons closely coupled units metabolism consume a lot ATPs process neurotransmission. metabolic substrates neurons, maintain high neuron, facilitate information transmission This article reviews characteristics glucose metabolism, lipid amino acid astrocytes. interactions between microglia were also detailed discussed. Finally, we classified analyzed role disorder occurrence development neurodegenerative diseases.

Language: Английский

---

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

Journal of Neurochemistry, Journal Year: 2023, Volume and Issue: 166(2), P. 109 - 137

Published: March 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

Language: Английский

---

Axonal energy metabolism, and the effects in aging and neurodegenerative diseases

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: July 20, 2023

Abstract Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of (NDAs), such as Alzheimer’s disease, Parkinson’s Huntington’s Amyotrophic lateral sclerosis. Glucose is the major brain fuel glucose hypometabolism has been observed regions vulnerable to NDAs. Many susceptible are topological central hub connectome, linked by densely interconnected long-range axons. Axons, key components have high metabolic needs support neurotransmission other essential activities. Long-range axons particularly injury, neurotoxin exposure, protein stress, lysosomal dysfunction, etc. Axonopathy often an early sign neurodegeneration. Recent ascribe axonal maintenance failures local dysregulation. With this review, we aim stimulate research exploring metabolically oriented neuroprotection strategies enhance or normalize bioenergetics NDA models. Here start summarizing evidence from human patients animal models reveal correlation between connectomic disintegration aging/NDAs. To encourage mechanistic investigations on how dysregulation occurs during aging/NDAs, first review current literature distinct subdomains: axon initial segments, myelinated arbors harboring pre-synaptic boutons. In each subdomain, focus organization, activity-dependent regulation system, external glial support. Second, mechanisms regulating nicotinamide adenine dinucleotide (NAD + ) homeostasis, molecule for energy metabolism processes, including NAD biosynthetic, recycling, consuming pathways. Third, highlight innate vulnerability connectome discuss its perturbation As deficits developing into NDAs, especially asymptomatic phase, they likely exaggerated further impaired energetic cost neural network hyperactivity, pathology. Future interrogating causal relationship vulnerability, axonopathy, amyloid/tau pathology, cognitive decline will provide fundamental knowledge therapeutic interventions.

Language: Английский

---

Inflammatory aspects of Alzheimer’s disease

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 148(1)

Published: Aug. 28, 2024

Language: Английский

---

The Glutamate/GABA‐Glutamine Cycle: Insights, Updates, and Advances

Journal of Neurochemistry, Journal Year: 2025, Volume and Issue: 169(3)

Published: March 1, 2025

ABSTRACT Synaptic homeostasis of the principal neurotransmitters glutamate and GABA is tightly regulated by an intricate metabolic coupling between neurons astrocytes known as glutamate/GABA‐glutamine cycle. In this cycle, take up from synapse convert these into glutamine. Astrocytic glutamine subsequently transferred to neurons, serving precursor for neuronal synthesis. The cycle integrates multiple cellular processes, including neurotransmitter release, uptake, synthesis, metabolism. All processes are deeply interdependent closely coupled energy Astrocytes display highly active mitochondrial oxidative metabolism several unique features, glycogen storage pyruvate carboxylation, which essential sustain continuous release. However, new roles oligodendrocytes microglia in recycling emerging. Malfunction can lead severe synaptic disruptions may be implicated brain diseases. Here, I review central aspects recent advances highlight how functionally connected critical functions First, overview glutamate, GABA, transport provided relation recycling. Then, reviewed, with a special emphasis on glial cells. Finally, discuss aberrant linked neurodegeneration disease, focusing astrocyte dysfunction lipid emerging pathological mechanisms. Instead viewing individual biochemical more holistic integrative approach needed advance our understanding modulates function both health disease. image

Language: Английский

---

Glucose Metabolism, Neural Cell Senescence and Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(8), P. 4351 - 4351

Published: April 14, 2022

Alzheimer’s disease (AD), an elderly neurodegenerative disorder with a high incidence and progressive memory decline, is one of the most expensive, lethal, burdening diseases. To date, pathogenesis AD has not been fully illustrated. Emerging studies have revealed that cellular senescence abnormal glucose metabolism in brain are early hallmarks AD. Moreover, disturbance patients may precede amyloid-β deposition or Tau protein phosphorylation. Thus, metabolic reprogramming targeting senescent microglia astrocytes be novel strategy for intervention treatment. Here, we recapitulate relationships between neural cell (e.g., insulin signaling, lactate metabolism) We then discuss potential perspective towards intervention, providing theoretical basis further exploration therapeutic approach toward

Language: Английский

---

Glial Glutamine Homeostasis in Health and Disease

Neurochemical Research, Journal Year: 2022, Volume and Issue: 48(4), P. 1100 - 1128

Published: Nov. 2, 2022

Language: Английский

---

Mitochondrial hypermetabolism precedes impaired autophagy and synaptic disorganization in App knock-in Alzheimer mouse models

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(9), P. 3966 - 3981

Published: Sept. 1, 2023

Accumulation of amyloid β-peptide (Aβ) is a driver Alzheimer's disease (AD). Amyloid precursor protein (App) knock-in mouse models recapitulate AD-associated Aβ pathology, allowing elucidation downstream effects accumulation and their temporal appearance upon progression. Here we have investigated the sequential onset AD-like pathologies in AppNL-F AppNL-G-F mice by time-course transcriptome analysis hippocampus, region severely affected AD. Strikingly, energy metabolism emerged as one most significantly altered pathways already at an early stage pathology. Functional experiments isolated mitochondria from hippocampus both confirmed upregulation oxidative phosphorylation driven activity mitochondrial complexes I, IV V, associated with higher susceptibility to damage Ca2+-overload. Upon increasing pathologies, brain shifts state hypometabolism reduced abundancy presynaptic terminals. These late-stage also displayed enlarged areas abnormal synaptic vesicles autophagosomes, latter ultimately leading local autophagy impairment synapses. In summary, report that Aβ-induced App key observed AD brain, our data herein adds comprehensive understanding including dysregulated synapses timewise find new therapeutic approaches for

Language: Английский

---

Astrocytes regulate inhibitory neurotransmission through GABA uptake, metabolism, and recycling

Essays in Biochemistry, Journal Year: 2023, Volume and Issue: 67(1), P. 77 - 91

Published: Feb. 21, 2023

Abstract Synaptic regulation of the primary inhibitory neurotransmitter γ-aminobutyric acid (GABA) is essential for brain function. Cerebral GABA homeostasis tightly regulated through multiple mechanisms and directly coupled to metabolic collaboration between neurons astrocytes. In this essay, we outline discuss fundamental roles astrocytes in regulating synaptic signaling. A major fraction removed from synapse by astrocytic uptake. Astrocytes utilize as a substrate support glutamine synthesis. The astrocyte-derived subsequently transferred where it serves precursor neuronal flow collectively termed GABA-glutamine cycle sustain synthesis certain areas, are even capable synthesizing releasing modulate transmission. majority oxidative metabolism takes place astrocytes, which also leads GABA-related metabolite γ-hydroxybutyric (GHB). physiological endogenous GHB remain unclear, but may be related tonic inhibition plasticity. Disrupted signaling dysfunctional astrocyte handling implicated several diseases including epilepsy Alzheimer’s disease. under control uptake, metabolism, recycling therefore serve relevant targets ameliorate pathological

Language: Английский

---