Mutations in the transcriptional regulator MeCP2 severely impact key cellular and molecular signatures of human astrocytes during maturation DOI Creative Commons
Jialin Sun,

Sivan Osenberg,

Austin Irwin

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(1), P. 111942 - 111942

Published: Jan. 1, 2023

Mutations in the MECP2 gene underlie a spectrum of neurodevelopmental disorders, most commonly Rett syndrome (RTT). We ask whether mutations interfere with human astrocyte developmental maturation, thereby affecting their ability to support neurons. Using human-based models, we show that RTT-causing greatly impact key role astrocytes regulating overall brain bioenergetics and these metabolic aberrations are likely mediated by dysfunctional mitochondria. During post-natal rely on neurons induce complex stellate morphology transcriptional changes. While cause cell-intrinsic landscape, surprisingly, they do not affect neuron-induced expression. Notably, however, unable develop mature due cell- non-cell-autonomous caused mutations. Thus, critically cellular molecular features and, hence, interact structural functional maturation

Language: Английский

Lactate in the brain: from metabolic end-product to signalling molecule DOI
Pierre J. Magistretti, Igor Allaman

Nature reviews. Neuroscience, Journal Year: 2018, Volume and Issue: 19(4), P. 235 - 249

Published: March 8, 2018

Language: Английский

Citations

952
In Vivo Evidence for a Lactate Gradient from Astrocytes to Neurons DOI Creative Commons
Philipp Mächler, Matthias T. Wyss,

Maha Elsayed

et al.

Cell Metabolism, Journal Year: 2015, Volume and Issue: 23(1), P. 94 - 102

Published: Nov. 19, 2015

Language: Английский

Citations

512
Glucose transporters in brain in health and disease DOI Creative Commons
Hermann Koepsell

Pflügers Archiv - European Journal of Physiology, Journal Year: 2020, Volume and Issue: 472(9), P. 1299 - 1343

Published: Aug. 13, 2020

Abstract Energy demand of neurons in brain that is covered by glucose supply from the blood ensured transporters capillaries and cells. In brain, facilitative diffusion GLUT1-6 GLUT8, Na + - d -glucose cotransporters SGLT1 are expressed. The mediate uptake across blood-brain barrier delivery to astrocytes neurons. They critically involved regulatory adaptations varying energy demands response differing neuronal activities supply. this review, a comprehensive overview about verified proposed roles cerebral during health diseases presented. Our current knowledge mainly based on experiments performed rodents. First, functional properties human expressed their locations described. Thereafter, physiological functions GLUT1, GLUT2, GLUT3, GLUT4, for neurons, sensing, central regulation glucohomeostasis, feeding behavior compiled, learning memory formation discussed. addition, described which changes relevant. These GLUT1 deficiency syndrome (GLUT1-SD), diabetes mellitus, Alzheimer’s disease (AD), stroke, traumatic injury (TBI). GLUT1-SD caused defect mutations GLUT1. Diabetes AD associated with changed expression transporter-related may contribute pathogenesis AD. Stroke TBI transporter influence clinical outcome.

Language: Английский

Citations

389
Modeling Alzheimer’s disease with iPSC-derived brain cells DOI Creative Commons

Jay Penney,

William T. Ralvenius, Li‐Huei Tsai

et al.

Molecular Psychiatry, Journal Year: 2019, Volume and Issue: 25(1), P. 148 - 167

Published: Aug. 7, 2019

Alzheimer’s disease is a devastating neurodegenerative disorder with no cure. Countless promising therapeutics have shown efficacy in rodent models yet failed to benefit human patients. While hope remains that earlier intervention existing will improve outcomes, it becoming increasingly clear new approaches understand and combat the pathophysiology of are needed. Human induced pluripotent stem cell (iPSC) technologies changed face preclinical research iPSC-derived types being utilized study an array conditions, including disease. All major brain can now be differentiated from iPSCs, while complex co-culture systems developed facilitate neuroscience research. Many cellular functions perturbed recapitulated using cells vitro, platforms beginning yield insights into interactions occur between during neurodegeneration. Further, iPSC-based genome editing tools critical understanding roles numerous genes mutations found modify risk past decade. still their relative infancy, these developing hold considerable promise push forward efforts other disorders.

Language: Английский

Citations

368
Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders DOI
Ashley N. Brandebura, Adrien Paumier, Tarik Seref Onur

et al.

Nature reviews. Neuroscience, Journal Year: 2022, Volume and Issue: 24(1), P. 23 - 39

Published: Oct. 31, 2022

Language: Английский

Citations

263
An astroglial basis of major depressive disorder? An overview DOI
Qian Wang, Wei Jie, Jihong Liu

et al.

Glia, Journal Year: 2017, Volume and Issue: 65(8), P. 1227 - 1250

Published: March 20, 2017

Abstract Depression is a chronic, recurring, and serious mood disorder that afflicts up to 20% of the global population. The monoamine hypothesis has dominated our understanding pharmacotherapy depression for more than half century; however, pathophysiology pathogenesis major lagged far behind. Astrocytes are most abundant versatile cells in brain, participating most, if not all, brain functions as both passive housekeeper an active player. Mounting evidence from clinical, preclinical post‐mortem studies revealed decrease number or density astrocytes morphological functional astroglial atrophy patients with depressive (MDD) animal models depression. Furthermore, currently available antidepressant treatments at least partially exert their therapeutic effects on astrocytes. More importantly, dysfunctional lead depressive‐like phenotypes animals. Together, current point pathology potential root cause MDD. Thus, shift neuron‐centric astrocyte‐centric MDD gained increasing attention during past two decades. Here we will summarize supporting disease astrocyte highlight previous promising strategies directly target development novel treatments.

Language: Английский

Citations

191
Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS DOI Creative Commons
Chun‐Cheih Chao, Cristina Gutiérrez‐Vázquez, Veit Rothhammer

et al.

Cell, Journal Year: 2019, Volume and Issue: 179(7), P. 1483 - 1498.e22

Published: Dec. 1, 2019

Language: Английский

Citations

161
Monocarboxylate transporter 4 (MCT4) is a high affinity transporter capable of exporting lactate in high-lactate microenvironments DOI Creative Commons

Yasna Contreras‐Baeza,

Pamela Y. Sandoval,

R.A. Alarcon

et al.

Journal of Biological Chemistry, Journal Year: 2019, Volume and Issue: 294(52), P. 20135 - 20147

Published: Nov. 12, 2019

Monocarboxylate transporter 4 (MCT4) is an H+-coupled symporter highly expressed in metastatic tumors and at inflammatory sites undergoing hypoxia or the Warburg effect. At these sites, extracellular lactate contributes to malignancy immune response evasion. Intriguingly, 30-40 mm, reported Km of MCT4 for more than 1 order magnitude higher physiological even pathological levels. not thought transport pyruvate. Here we have characterized cell pyruvate dynamics using FRET sensors Laconic Pyronic. Dominant permeability was demonstrated various types by pharmacological means CRISPR/Cas9-mediated deletion. Respective values uptake were 1.7, 1.2, 0.7 mm MDA-MB-231 cells, macrophages, HEK293 cells expressing recombinant MCT4. In exhibited a 4.2 as opposed >150 previously. Parallel assays with pH-sensitive dye 2',7'-bis-(carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) indicated that previous estimates based on substrate-induced acidification severely biased confounding pH-regulatory mechanisms. Numerical simulation revised kinetic parameters revealed MCT4, but related transporters MCT1 MCT2, endows ability export high-lactate microenvironments. conclusion, high-affinity physiologically relevant affinity

Language: Английский

Citations

152
Decoupling astrocytes in adult mice impairs synaptic plasticity and spatial learning DOI Creative Commons
Ladina Hösli,

Noemi Binini,

Kim David Ferrari

et al.

Cell Reports, Journal Year: 2022, Volume and Issue: 38(10), P. 110484 - 110484

Published: March 1, 2022

The mechanisms by which astrocytes modulate neural homeostasis, synaptic plasticity, and memory are still poorly explored. Astrocytes form large intercellular networks gap junction coupling, mainly composed of two channel proteins, connexin 30 (Cx30) 43 (Cx43). To circumvent developmental perturbations to test whether astrocytic coupling is required for hippocampal circuit function behavior, we generate study inducible, astrocyte-specific Cx30 Cx43 double knockouts. Surprisingly, disrupting in adult mice results broad activation microglia, without obvious signs pathology. We show that CA1 neuron excitability, excitatory transmission, long-term potentiation significantly affected. Moreover, behavioral inspection reveals deficits sensorimotor performance a complete lack spatial learning memory. Together, our findings establish connexins an intact astroglial network the brain vital cognition.

Language: Английский

Citations

78
Acetate enables metabolic fitness and cognitive performance during sleep disruption DOI

Qinqin He,

Liwei Ji,

Yanyan Wang

et al.

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(9), P. 1998 - 2014.e15

Published: Aug. 19, 2024

Language: Английский

Citations

17