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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Lysosomal acidification dysfunction in microglia: an emerging pathogenic mechanism of neuroinflammation and neurodegeneration

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Авг. 5, 2023

Microglia are the resident innate immune cells in brain with a major role orchestrating responses. They also provide frontline of host defense central nervous system (CNS) through their active phagocytic capability. Being professional phagocyte, microglia participate and autophagic clearance cellular waste debris as well toxic protein aggregates, which relies on optimal lysosomal acidification function. Defective microglial leads to impaired functions result perpetuation neuroinflammation progression neurodegeneration. Reacidification lysosomes has been shown reverse neurodegenerative pathology Alzheimer's disease. In this review, we summarize key factors mechanisms contributing impairment associated dysfunction microglia, how these defects contribute We further discuss techniques monitor pH therapeutic agents that can reacidify under disease conditions. Finally, propose future directions investigate lysosome-mitochondria crosstalk neuron-glia interaction for more comprehensive understanding its broader CNS physiological pathological implications.

Язык: Английский

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Metabolic reprogramming and polarization of microglia in Parkinson’s disease: Role of inflammasome and iron

Ageing Research Reviews, Год журнала: 2023, Номер 90, С. 102032 - 102032

Опубликована: Авг. 10, 2023

Язык: Английский

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Neuroprotection in glaucoma: Mechanisms beyond intraocular pressure lowering

Molecular Aspects of Medicine, Год журнала: 2023, Номер 92, С. 101193 - 101193

Опубликована: Июнь 16, 2023

Glaucoma is a common, complex, multifactorial neurodegenerative disease characterized by progressive dysfunction and then loss of retinal ganglion cells, the output neurons retina. most common cause irreversible blindness affects ∼80 million people worldwide with many more undiagnosed. The major risk factors for glaucoma are genetics, age, elevated intraocular pressure. Current strategies only target pressure management do not directly processes occurring at level cell. Despite to manage pressure, as 40% patients progress in least one eye during their lifetime. As such, neuroprotective that cell these great therapeutic need. This review will cover recent advances from basic biology on-going clinical trials neuroprotection covering degenerative mechanisms, metabolism, insulin signaling, mTOR, axon transport, apoptosis, autophagy, neuroinflammation. With an increased understanding both mechanisms disease, we closer than ever strategy glaucoma.

Язык: Английский

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Aging microglia

Cellular and Molecular Life Sciences, Год журнала: 2023, Номер 80(5)

Опубликована: Апрель 21, 2023

Abstract Microglia are the tissue-resident macrophage population of brain, specialized in supporting CNS environment and protecting it from endogenous exogenous insults. Nonetheless, their function declines with age, ways that remain to be fully elucidated. Given critical role played by microglia neurodegenerative diseases, a better understanding aging phenotype is an essential prerequisite designing preventive therapeutic strategies. In this review, we discuss most recent literature on aging, comparing findings rodent models human subjects.

Язык: Английский

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TREM2: Potential therapeutic targeting of microglia for Alzheimer's disease

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 165, С. 115218 - 115218

Опубликована: Июль 29, 2023

Alzheimer's disease (AD) is the most common neurodegenerative disease, resulting in loss of cognitive ability and memory. However, there no specific treatment to mechanistically inhibit progression drugs only provide symptom relief do not fundamentally reverse AD. Current studies show that triggering receptor expressed on myeloid cells 2 (TREM2) predominantly microglia central nervous system (CNS) involved proliferation, survival, migration phagocytosis. The current academic view suggests TREM2 its ligands have CNS protective effects Specifically, acts by regulating function promoting clearance neuronal toxic substances abnormal proteins microglia. In addition, also inflammatory response cell signaling pathways, affecting immune regulatory role Although relationship between has been extensively studied, mechanism action fully understood. purpose this review a comprehensive analysis research TREM2, including regulation response, lipid metabolism phagocytosis AD, explore potential application prospects as well limitations targeting for

Язык: Английский

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The reciprocal interactions between microglia and T cells in Parkinson’s disease: a double-edged sword

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Фев. 12, 2023

In Parkinson's disease (PD), neurotoxic microglia, Th1 cells, and Th17 cells are overactivated. Overactivation of these immune exacerbates the process leads to pathological development pro-inflammatory cytokines, chemokines, contact-killing compounds, causing loss dopaminergic neurons. So far, we have mainly focused on role specific class in PD while neglecting impact interactions among disease. Therefore, this review demonstrates reciprocal interplays between microglia T associated subpopulations through cytokine chemokine production that impair and/or protect PD. Furthermore, potential targets models neuroinflammation highlighted provide new ideas/directions for future research.

Язык: Английский

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Microglial phagocytosis dysfunction in stroke is driven by energy depletion and induction of autophagy

Autophagy, Год журнала: 2023, Номер 19(7), С. 1952 - 1981

Опубликована: Янв. 9, 2023

Microglial phagocytosis of apoptotic debris prevents buildup damage neighbor neurons and inflammatory responses. Whereas microglia are very competent phagocytes under physiological conditions, we report their dysfunction in mouse preclinical monkey models stroke (macaques marmosets) by transient occlusion the medial cerebral artery (tMCAo). By analyzing recently published bulk single cell RNA sequencing databases, show that was not explained transcriptional changes. In contrast, demonstrate impairment both engulfment degradation related to energy depletion triggered oxygen nutrient deprivation (OND), which led reduced process motility, lysosomal exhaustion, induction a protective macroautophagy/autophagy response microglia. Basal autophagy, charge removing recycling intracellular elements, critical maintain microglial physiology, including survival phagocytosis, as determined vivo vitro using pharmacological transgenic approaches. Notably, autophagy inducer rapamycin partially prevented induced tMCAo but OND vitro, where it even had detrimental effect on microglia, suggesting modulating optimal levels may be hard achieve goal. Nonetheless, our results interventions, acting directly or indirectly brain environment, have potential recover efficiency diseased brain. We propose is therapeutic target yet explored other disorders provide evidence can modulated rapamycin.Abbreviations: AIF1/IBA1: allograft factor 1; AMBRA1: autophagy/beclin 1 regulator ATG4B: 4B, cysteine peptidase; ATP: adenosine triphosphate; BECN1: beclin 1, related; CASP3: caspase 3; CBF: blood flow; CCA: common carotid artery; CCR2: chemokine (C-C motif) receptor 2; CIR: cranial irradiation; Csf1r/v-fms: colony stimulating receptor; CX3CR1: (C-X3-C DAPI: 4',6-diamidino-2-phenylindole; DG: dentate gyrus; GO: Gene Ontology; HBSS: Hanks' balanced salt solution; HI: hypoxia-ischemia; LAMP1: lysosomal-associated membrane protein MAP1LC3/LC3: microtubule-associated light chain MCA: MTOR: mechanistic kinase; OND: deprivation; Ph/A coupling: phagocytosis-apoptosis coupling; Ph capacity: phagocytic capacity; index: index; SQSTM1: sequestosome RNA-Seq: sequencing; TEM: transmission electron microscopy; tMCAo: occlusion; ULK1: unc-51 like kinase 1.

Язык: Английский

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Microglial morphometric analysis: so many options, so little consistency

Frontiers in Neuroinformatics, Год журнала: 2023, Номер 17

Опубликована: Авг. 10, 2023

Quantification of microglial activation through morphometric analysis has long been a staple the neuroimmunologist’s toolkit. Microglial morphological phenomics can be conducted either manual classification or constructing digital skeleton and extracting data from it. Multiple open-access paid software packages are available to generate these skeletons via semi-automated and/or fully automated methods with varying degrees accuracy. Despite advancements in morphometrics (quantitative measures cellular morphology), there limited development tools analyze datasets they generate, particular those containing parameters tens thousands cells analyzed by pipelines. In this review, we compare critique approaches using cluster machine learning driven predictive algorithms that have developed tackle large datasets, propose improvements for methods. particular, highlight need commitment open science groups developing classifiers. Furthermore, call attention communication between strong engineering/computer background neuroimmunologists produce effective analytical simplified operability if see their wide-spread adoption glia biology community.

Язык: Английский

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Reduced secretion of LCN2 (lipocalin 2) from reactive astrocytes through autophagic and proteasomal regulation alleviates inflammatory stress and neuronal damage

Autophagy, Год журнала: 2023, Номер 19(8), С. 2296 - 2317

Опубликована: Фев. 14, 2023

LCN2/neutrophil gelatinase-associated lipocalin/24p3 (lipocalin 2) is a secretory protein that acts as mammalian bacteriostatic molecule. Under neuroinflammatory stress conditions, LCN2 produced and secreted by activated microglia reactive astrocytes, resulting in neuronal apoptosis. However, it remains largely unknown whether inflammatory loss can be minimized modulating production secretion. Here, we first demonstrated was from which were stimulated treatment with lipopolysaccharide (LPS) an stressor. Notably, found two effective conditions led to the reduction of induced levels astrocytes: proteasome inhibition macroautophagic/autophagic flux activation. Mechanistically, suppresses NFKB/NF-κB activation through NFKBIA/IκBα stabilization primary even under downregulation Lcn2 expression. In contrast, autophagic via MTOR reduced intracellular its pre-secretory degradation. addition, N-terminal signal peptide critical for secretion degradation, suggesting these pathways may mechanistically coupled. Finally, observed LPS-induced astrocyte-cultured medium above-mentioned increased viability, stress.Abbreviations: ACM, astrocyte-conditioned medium; ALP, autophagy-lysosome pathway; BAF, bafilomycin A1; BTZ, bortezomib; CHX, cycloheximide; CNS, central nervous system; ER, endoplasmic reticulum; GFAP, glial fibrillary acidic protein; GFP, green fluorescent JAK, Janus kinase; KD, knockdown; LCN2, lipocalin 2; LPS, lipopolysaccharide; MACS, magnetic-activated cell sorting; MAP1LC3/LC3, microtubule-associated 1 light chain 3; MTOR, mechanistic target rapamycin NFKB/NF-κB, nuclear factor kappa polypeptide gene enhancer B cells 1, p105; NFKBIA/IκBα, inhibitor, alpha; OVEX, overexpression; SLC22A17, solute carrier family 22 member 17; SP, peptide; SQSTM1, sequestosome 1; STAT3, transducer activator transcription TNF/TNF-α, tumor necrosis factor; TUBA, tubulin, TUBB3/β3-TUB, beta 3 class III; UB, ubiquitin; UPS, ubiquitin-proteasome system

Язык: Английский

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