Astrocyte Depletion Impairs Redox Homeostasis and Triggers Neuronal Loss in the Adult CNS

Schreiner, Bettina; Romanelli, Elisa; Liberski, Paweł P.; Ingold-Heppner, Barbara; Sobottka, Bettina; Hartwig, Tom; Chandrasekar, Vijay; Johannssen, Helge C.; Zeilhofer, Hanns Ulrich; Aguzzi, Adriano; Heppner, Frank L.; Kerschensteiner, Martin; Becher, Burkhard

doi:10.1016/j.celrep.2015.07.051

Cited by 106 publications

(87 citation statements)

References 34 publications

(37 reference statements)

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“…Astrocytes are essential to neuronal survive and synaptic activity. Thus, astrocyte damage may lead to pathologies [65], considering that astrocyte depletion seems to be correlated with neuronal loss [66]. The results of histology and immunohistochemistry suggest that the behavioral change observed is due to cell loss in key cerebellar areas responsible for movement coordination.…”

Section: Discussionmentioning

confidence: 97%

D-Galactose Causes Motor Coordination Impairment, and Histological and Biochemical Changes in the Cerebellum of Rats

et al. 2016

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Classical galactosemia is an inborn error of carbohydrate metabolism in which patients accumulate high concentration of galactose in the brain. The most common treatment is a galactose-restricted diet. However, even treated patients develop several complications. One of the most common symptoms is motor coordination impairment, including affected gait, balance, and speech, as well as tremor and ataxia. In the present study, we investigated the effects of intracerebroventricular galactose administration on motor coordination, as well as on histological and biochemical parameters in cerebellum of adult rats. Wistar rats received 5 μL of galactose (4 mM) or saline by intracerebroventricular injection. The animals performed the beam walking test at 1 and 24 h after galactose administration. Histological and biochemical parameters were performed 24 h after the injections. The results showed motor coordination impairment at 24 h after galactose injection. Galactose also decreased the number of cells in the molecular and granular layers of the cerebellum. The immunohistochemistry results suggest that the cell types lost by galactose are neurons and astrocytes in the spinocerebellum and neurons in the cerebrocerebellum. Galactose increased active caspase-3 immunocontent and acetylcholinesterase activity, decreased acetylcholinesterase immunocontent, glutathione, and BDNF levels, as well as caused protein and DNA damage. Our results suggest that galactose induces histological and biochemical changes in cerebellum, which can be associated with motor coordination impairment.

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Section: Discussionmentioning

confidence: 97%

D-Galactose Causes Motor Coordination Impairment, and Histological and Biochemical Changes in the Cerebellum of Rats

et al. 2016

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“…As astrocytic processes cover almost completely the brain capillaries, astrocytes are rapidly exposed to any substance crossing from blood through the blood-brain barrier into the brain [21]. Astrocytes are considered to have important functions for the metabolism of the brain [22,23], in the defence of the brain against toxins and oxidative stress [24][25][26] and in the metal homeostasis of the brain [27][28][29].…”

Section: Introductionmentioning

confidence: 99%

The Antidiabetic Drug Metformin Stimulates Glycolytic Lactate Production in Cultured Primary Rat Astrocytes

2015

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Metformin is the most frequently used drug for the treatment of type 2 diabetes in humans. However, only little is known about effects of metformin on brain metabolism. To investigate potential metabolic consequences of an exposure of brain cells to metformin, we incubated rat astrocyte-rich primary cultures with this compound. Metformin in concentrations of up to 30 mM did not acutely compromise the viability of astrocytes, but caused a time- and concentration-dependent increase in cellular glucose consumption and lactate production. For acute incubations in the hour range, the presence of 10 mM metformin doubled the glycolytic flux, while already 1 mM metformin doubled glycolytic flux during incubation for 24 h. In addition to metformin, also other guanidino compounds increased astrocytic lactate production. After 4 h of incubation, half-maximal stimulation of glycolysis was observed for metformin, guanidine and phenformin at concentrations of around 3 mM, 3 mM and 30 µM, respectively. The acute stimulation of glycolytic lactate production by metformin was persistent after removal of extracellular metformin and was also observed, if glucose was absent from the incubation medium or replaced by other hexoses. The metformin-induced stimulation of glycolytic flux was not prevented by compound C, an inhibitor of AMP-dependent protein kinase, nor was it additive to the stimulation of glycolytic flux caused by respiratory chain inhibitors. These data demonstrate that the antidiabetic drug metformin has the potential to strongly activate glycolytic lactate production in brain astrocytes.

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Section: Introductionmentioning

confidence: 99%

“…Whether the NOX-generated oxidants are used for pathogen eradication or redox signalling purposes, it is important for microglia to have a sophisticated battery of antioxidant proteins (Table 1), which serve to keep the redox homeostasis of the cells, and to avoid excessive oxidative damage to constituent macromolecules. Also, astrocytes express many antioxidant proteins at high levels, and astrocytes are essential for the maintenance of the global redox balance in the CNS under normal (Schreiner et al, 2015) or pathological conditions (Gan et al, 2012).Several non-cell-autonomous brain diseases of the neuropsychiatric spectrum have been identified, where genetic (Schafer et al, 2012;Zhang et al, 2014a), and microglia may also guide differentiation and axon outgrowth of maturing neurons (Squarzoni et al, 2014).Reciprocal interactions between T-cells and different phagocyte compartments of the brain including microglia have been shown to modulate cognitive processes on a more global scale (Ziv et al, 2006;Derecki et al, 2010).In the following, we will address how microglial oxidant production and associated antioxidants function physiologically to maintain and support the neuronal circuitry and communication with other CNS cell types and pathologically to cause oxidative damage and derangement of autocrine and paracrine redox signalling. In combination with the accompanying review (Haslund-Vinding et al, 2017), we place the emphasis on the family of NADPH oxidases (NOX family) in oxidant production, and the GSH-thioredoxin antioxidant system required for the transient thiol modification of target proteins for signalling purposes.…”

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confidence: 99%

Microglia antioxidant systems and redox signalling

Vilhardt¹,

Haslund-vinding

Jaquet³

et al. 2016

British J Pharmacology

109

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For many years, microglia, the resident CNS macrophages, have been considered only in the context of pathology, but microglia are also glial cells with important physiological functions. Microglia-derived oxidant production by NADPH oxidase (NOX2) is implicated in many CNS disorders. Oxidants do not stand alone, however, and are not always pernicious. We discuss in general terms, and where available in microglia, GSH synthesis and relation to cystine import and glutamate export, and the thioredoxin system as the most important antioxidative defence mechanism, and further, we discuss in the context of protein thiolation of target redox proteins the necessity for tightly localized, timed and confined oxidant production to work in concert with antioxidant proteins to promote redox signalling. NOX2-mediated redox signalling modulates the acquisition of the classical or alternative microglia activation phenotypes by regulating major transcriptional programs mediated through NF-κB and Nrf2, major regulators of the inflammatory and antioxidant response respectively. As both antioxidants and NOX-derived oxidants are co-secreted, in some instances redox signalling may extend to neighboring cells through modification of surface or cytosolic target proteins. We consider a role for microglia NOX-derived oxidants in paracrine modification of synaptic function through long term depression and in the communication with the adaptive immune system. There is little doubt that a continued foray into the functions of the antioxidant response in microglia will reveal antioxidant proteins as dynamic players in redox signalling, which in concert with NOX-derived oxidants fulfil important roles in the autocrine or paracrine regulation of essential enzymes or transcriptional programs. LINKED ARTICLESThis article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc Abbreviations Aβ, amyloid-β peptide 1-42; DAMP, damage-associated molecular pattern molecules; GCL, glutamate cysteine ligase; GPx, GSH peroxidase; HNE, 4-hydroxy-2-nonenal; HO-1, haem oxygenase-1; KEAP1, Kelch-like ECH-associated protein; LTD, long-term depression; PLA 2 , phospholipase A 2 ; Prx, peroxiredoxins; Trx, thioredoxin; TrxR, thioredoxin reductase; xCT, cystine-glutamate exchanger IntroductionMicroglia, the resident immune cells of the brain, are exquisitely sensitive cells, which through a large and unique repertoire of sensing cell surface receptors (Hickman et al., 2013) responding to ligands of exogenous or endogenous nature (Kettenmann et al., 2013) continuously survey the brain parenchyma for even the smallest deviation from homeostasis. When the fine, motile processes of microglia encounter a problem, microglia assume an activation phenotype adapted to the quick resolution of damage and return to homeostasis. If instigating insults cannot be resolved, chronic microglia activation ensues. The differing nature of...

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Astrocyte Depletion Impairs Redox Homeostasis and Triggers Neuronal Loss in the Adult CNS

Cited by 106 publications

References 34 publications

D-Galactose Causes Motor Coordination Impairment, and Histological and Biochemical Changes in the Cerebellum of Rats

D-Galactose Causes Motor Coordination Impairment, and Histological and Biochemical Changes in the Cerebellum of Rats

The Antidiabetic Drug Metformin Stimulates Glycolytic Lactate Production in Cultured Primary Rat Astrocytes

Microglia antioxidant systems and redox signalling

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