Isolation of glia from Alzheimer's mice reveals inflammation and dysfunction

Orre, Marie; Kamphuis, Willem; Osborn, Lana M.; Jansen, Anne H. P.; Kooijman, Lieneke; Bossers, Koen; Hol, Elly M.

doi:10.1016/j.neurobiolaging.2014.06.004

Cited by 352 publications

(383 citation statements)

References 53 publications

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“…It is often assumed that astrocyte functions may get out of the balance in pathological situations and then compromise neuronal survival (Buffo et al 2010). In support of this, altered (i.e., activated) astrocytes are found in many neurodegenerative diseases (Forno et al 1992;Medeiros and LaFerla 2013;Orre et al 2014), in intoxications, and after traumatic injury (Silver and Miller 2004).…”

Section: Introductionmentioning

confidence: 80%

“…Specific target cells in the central nervous system include microglia, a cell type related to peripheral macrophages but of distinctly different developmental origin (Gomez Perdiguero et al 2015), and astrocytes, an often neglected cell population that has a moderate abundance in rodent brains, but exceeds the number of neurons in human brain by threefold to tenfold (Cahoy et al 2008;Volterra and Meldolesi 2005). Astrocytes have a peculiar double function, as major neurosupportive cell population in the healthy brain, and as powerful inflammatory cells that may exert detrimental effects in disease situations (Allen and Barres 2009;Maragakis and Rothstein 2006;Orre et al 2014;Sofroniew and Vinters 2010). Besides a general maintenance of brain homeostasis, astrocytes can protect neurons in multiple ways.…”

Section: Introductionmentioning

confidence: 99%

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Switching from astrocytic neuroprotection to neurodegeneration by cytokine stimulation

et al. 2016

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were involved in this neurodegeneration. The neurotoxicity-mediating effect of IMA was faithfully reproduced by human astrocytes. Moreover, glia-dependent toxicity was also observed, when IMA cultures were stimulated with CM, and the culture medium was transferred to neurons. Such neurotoxicity was prevented when astrocytes were treated by p38 kinase inhibitors or dexamethasone, whereas such compounds had no effect when added to neurons. Conversely, treatment of neurons with five different drugs, including resveratrol and CEP1347, prevented toxicity of astrocyte supernatants. Thus, the sequential IMA-LUHMES neuroinflammation model is suitable for separate profiling of both glial-directed and directly neuroprotective strategies. Moreover, direct evaluation in co-cultures of the same cells allows for testing of therapeutic effectiveness in more complex settings, in which astrocytes affect pharmacological properties of neurons.Keywords LUHMES · Astrocyte · p38 kinase · Neuroinflammation · Neuropharmacology Abstract Astrocytes, the largest cell population in the human brain, are powerful inflammatory effectors. Several studies have examined the interaction of activated astrocytes with neurons, but little is known yet about human neurotoxicity under such situations and about strategies of neuronal rescue. To address this question, immortalized murine astrocytes (IMA) were combined with human LUHMES neurons and stimulated with an inflammatory (TNF, IL-1) cytokine mix (CM). Neurotoxicity was studied both in co-cultures and in monocultures after transfer of conditioned medium from activated IMA. Interventions with >20 drugs were used to profile the model system. Control IMA supported neurons and protected them from neurotoxicants. Inflammatory activation reduced this protection, and prolonged exposure of co-cultures to CM triggered neurotoxicity. Neither the added cytokines nor the release of NO from astrocytes Liudmila Efremova and Petra Chovancova have contributed equally to this study.

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Section: Introductionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Switching from astrocytic neuroprotection to neurodegeneration by cytokine stimulation

et al. 2016

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“…Increased cerebral levels of Aβ peptides and their subsequent deposition lead to the activation of the surrounding microglia and astrocytes (Li et al, 2011). Upon activation, both microglia and astrocytes release pro‐ and anti‐inflammatory mediators, thereby establishing a chronic parenchymal inflammation (Orre et al, 2014). Chronic inflammatory stimulation of astrocytes reduces their capacity to release neurotrophic factors, for example glia‐derived neurotrophic factor, possibly contributing to cognitive decline in AD (Parpura et al, 2012).…”

Section: Astrocytes In the Diseased Brain Are Central To Neuropathologymentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

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“…In astrocytes purified (by fluorescence activated cell sorting) from the 15-18 month old APPswe/PS1dE9 mice, a substantial increase in "calcium ion binding" gene ontology class genes was detected [139].…”

Section: Ca 2+ Signalling In Ad Astrocytesmentioning

confidence: 99%

Astroglial calcium signalling in Alzheimer's disease

Verkhratsky

Rodriguez-Arellano

Parpura

et al. 2017

Biochemical and Biophysical Research Communications

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Neuroglial contribution to Alzheimer's disease (AD) is pathologically relevant and highly heterogeneous. Reactive astrogliosis and activation of microglia contribute to neuroinflammation, whereas astroglial and oligodendroglial atrophy affect synaptic transmission and underlie the overall disruption of the central nervous system (CNS) connectome. Astroglial function is tightly integrated with the intracellular ionic signalling mediated by complex dynamics of cytosolic concentrations of free Ca 2+ and Na + . Astroglial ionic signalling is mediated by plasmalemmal ion channels, mainly associated with ionotropic receptors, pumps and solute carrier transporters, and by intracellular organelles comprised of the endoplasmic reticulum and mitochondria. The relative contribution of these molecular cascades/organelles can be plastically remodelled in development and under environmental stress. In AD astroglial Ca 2+ signalling undergoes substantial reorganisation due to an abnormal regulation of expression of Ca 2+ handling molecular cascades.

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Isolation of glia from Alzheimer's mice reveals inflammation and dysfunction

Cited by 352 publications

References 53 publications

Switching from astrocytic neuroprotection to neurodegeneration by cytokine stimulation

Switching from astrocytic neuroprotection to neurodegeneration by cytokine stimulation

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Astroglial calcium signalling in Alzheimer's disease

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