Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing

Nature Reviews Drug Discovery, Journal Year: 2020, Volume and Issue: 19(9), P. 609 - 633

Published: July 24, 2020

Language: Английский

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Lactate metabolism in human health and disease

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Sept. 1, 2022

Abstract The current understanding of lactate extends from its origins as a byproduct glycolysis to role in tumor metabolism, identified by studies on the Warburg effect. shuttle hypothesis suggests that plays an important bridging signaling molecule coordinates among different cells, organs and tissues. Lactylation is posttranslational modification initially reported Professor Yingming Zhao’s research group 2019. Subsequent confirmed lactylation vital component function involved proliferation, neural excitation, inflammation other biological processes. An indispensable substance for various physiological cellular functions, regulatory aspects energy metabolism signal transduction. Therefore, comprehensive review summary presented clarify disease provide reference direction future research. This offers systematic overview homeostasis roles pathological processes, well effects diseases, particularly cancer.

Language: Английский

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Astrocyte-neuron metabolic cooperation shapes brain activity

Cell Metabolism, Journal Year: 2021, Volume and Issue: 33(8), P. 1546 - 1564

Published: Aug. 1, 2021

Language: Английский

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Glutamate metabolism and recycling at the excitatory synapse in health and neurodegeneration

Neuropharmacology, Journal Year: 2021, Volume and Issue: 196, P. 108719 - 108719

Published: July 15, 2021

Glutamate is the primary excitatory neurotransmitter of brain. Cellular homeostasis glutamate paramount importance for normal brain function and relies on an intricate metabolic collaboration between neurons astrocytes. extensively recycled astrocytes in a process known as glutamate-glutamine cycle. The recycling closely linked to energy metabolism essential sustain glutamatergic neurotransmission. However, considerable amount also metabolized serves hub connecting glucose amino acid both Disruptions clearance, leading neuronal overstimulation excitotoxicity, have been implicated several neurodegenerative diseases. Furthermore, link gaining attention neurological conditions. In this review, we provide overview dynamics synaptic underlying processes with cellular focus particular, review recently discovered role uptake discuss current advances context Alzheimer's disease Huntington's disease. Understanding regulation glutamate-dependent at synapse will not only increase our insight into mechanisms homeostasis, but may reveal new targets ameliorate neurodegeneration. This article part Neuropharmacology Special Issue 'Glutamate Receptors - Glutamatergic Synapse'.

Language: Английский

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Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Jan. 17, 2022

The ketogenic diet (KD) is a high-fat, adequate-protein, and very-low-carbohydrate regimen that mimics the metabolism of fasting state to induce production ketone bodies. KD has long been established as remarkably successful dietary approach for treatment intractable epilepsy increasingly garnered research attention rapidly in past decade, subject emerging evidence promising therapeutic potential various diseases, besides epilepsy, from obesity malignancies. In this review, we summarize experimental and/or clinical efficacy safety different discuss possible mechanisms action based on recent advances understanding influence at cellular molecular levels. We emphasize may function through multiple mechanisms, which remain be further elucidated. challenges future directions implementation spectrum diseases have discussed. suggest that, with encouraging effects increasing insights into action, randomized controlled trials should conducted elucidate foundation use KD.

Language: Английский

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Microglial metabolic flexibility supports immune surveillance of the brain parenchyma

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: March 25, 2020

Microglia are highly motile cells that continuously monitor the brain environment and respond to damage-associated cues. While glucose is main energy substrate used by neurons in brain, nutrients metabolized microglia support surveillance of parenchyma remain unexplored. Here, we use fluorescence lifetime imaging intracellular NAD(P)H time-lapse two-photon microglial dynamics vivo situ, show unique aspects metabolic signature brain. metabolically flexible can rapidly adapt consume glutamine as an alternative fuel absence glucose. During insulin-induced hypoglycemia or aglycemia acute slices, glutaminolysis supports maintenance process motility damage-sensing functions. This shift sustains mitochondrial metabolism requires mTOR-dependent signaling. remarkable plasticity allows maintain their critical phagocytic roles, even after neuroenergetic homeostasis compromised.

Language: Английский

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Protein lactylation induced by neural excitation

Cell Reports, Journal Year: 2021, Volume and Issue: 37(2), P. 109820 - 109820

Published: Oct. 1, 2021

Lactate has diverse roles in the brain at molecular and behavioral levels under physiological pathophysiological conditions. This study investigates whether lysine lactylation (Kla), a lactate-derived post-translational modification macrophages, occurs cells if it does, Kla is induced by stimuli that accompany changes lactate levels. Here, we show regulated neural excitation social stress, with parallel These increase Kla, which associated expression of neuronal activity marker c-Fos, as well decreased behavior increased anxiety-like stress model. In addition, identify 63 candidate lysine-lactylated proteins find preferentially increases histone H1 Kla. may open an avenue for exploration role activity-induced mediated protein brain.

Language: Английский

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Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood–brain barrier

Fluids and Barriers of the CNS, Journal Year: 2018, Volume and Issue: 15(1)

Published: Oct. 19, 2018

This review considers efflux of substances from brain parenchyma quantified as values clearances (CL, stated in µL g−1 min−1). Total clearance a substance is the sum for all available routes including perivascular pathways and blood–brain barrier. Perivascular contributes to water-soluble substances. Substances leaving via may enter cerebrospinal fluid (CSF) or lymph. These are also involved entry CSF. However, evidence demonstrating net flow inwards along arteries then outwards veins (the glymphatic hypothesis) still lacking. CLperivascular, that routes, has been measured by following fate exogenously applied labelled tracer amounts sucrose, inulin serum albumin, which not metabolized eliminated across With these total CL ≅ 1 have measured. at least partly other i.e. barrier, higher values. crossing barrier do so passive, non-specific means with CLblood-brain ranging < 0.01 > 1000 water CO2. many small solutes predictable their oil/water partition molecular weight. Transporters specific glucose, lactate polar substrates facilitate producing 50. The principal route movement Na+ Cl− ions probably paracellular through tight junctions between endothelial cells ~ 1. There large fluxes amino acids into out but only observed suggesting substantial reuse essential α-ketoacids within brain. Amyloid-β efflux, measurably faster than inulin, primarily leaves this be important amyloid-β reaches arterial walls resulting cerebral amyloid angiopathy.

Language: Английский

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Glucose, glycolysis, and neurodegenerative diseases

Journal of Cellular Physiology, Journal Year: 2020, Volume and Issue: 235(11), P. 7653 - 7662

Published: April 2, 2020

Abstract Prolonged survival of a typical postmitotic neuron hinges on balance between multiple processes, among these are sustenance ATP production and protection against reactive oxygen species. In neuropathological conditions, mitochondrial defects often lead to both drop in levels, as well increase species from inefficient electron transport processes NADPH‐oxidases activities. The former resulted the phenomenon compensatory aerobic glycolysis. latter stretches capacity cell's redox buffering capacity, may damages key enzymes involved energy metabolism. Several recent reports have indicated that enhancing glucose availability uptake, increasing glycolytic flux via pharmacological or genetic manipulation enzymes, could be protective animal models several major neurodegenerative diseases, including Parkinson's disease, Huntington's Amyotrophic lateral sclerosis. Activation canonical Wnt signaling, which improves disease symptoms mouse Alzheimer's also appears work an elevation enhance Here, I discuss findings possible underlying mechanisms how uptake glycolysis neuroprotective. Increased would help alleviate deficiency, ATP's hydrotropic effect solubility clearance toxic aggregates prevalent many diseases. Furthermore, channeling into Pentose Phosphate Pathway cell.

Language: Английский

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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

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