Neurological Diseases as Primary Gliopathies: A Reassessment of Neurocentrism

Verkhratsky, Alexei; Sofroniew, Michael V.; Messing, Albee; Delanerolle, Nihal; Rempe, David A.; Rodrı́guez, José J.; Nedergaard, Maiken

doi:10.1042/an20120010

Cited by 223 publications

(203 citation statements)

References 207 publications

(276 reference statements)

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“…Pathological potential of astroglia in various neurological diseases has been widely recognised by Rudolf Virchow, Ramón y Cajal, Pío del Río Hortega and Alois Alzheimer [63][64][65]; the interest in neuroglia in neuropathology has been greatly reinvigorated in the most recent decade [66][67][68][69][70][71]. Astrocytes contribute to every type of neuropathology, and this contribution is complex and context specific.…”

Section: Astroglia In Neurological Diseasesmentioning

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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Section: Astroglia In Neurological Diseasesmentioning

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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“…3 Although AD and ALS possess different etiologies, a commonality between these two diseases is the role of astrocytes in neurodegeneration. 4,5 Dysfunctional neuron-astrocyte crosstalk is known to be a central feature of neurodegenerative diseases. 6,7 Astrocytes exert both toxic and protective effects on neurons in a contextdependent manner.…”

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confidence: 99%

“…15 Thus, development of therapies targeting astrocytes is a subject of intense research. 4,5 Cellular senescence is characterized by proliferation arrest after extensive cell divisions or upon cellular stresses. The characteristics of cellular senescence include enlarged cell morphology, upregulation of cell cycle inhibitors p16 INK4 (ref.…”

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confidence: 99%

p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration

et al. 2016

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Bidirectional interactions between astrocytes and neurons have physiological roles in the central nervous system and an altered state or dysfunction of such interactions may be associated with neurodegenerative diseases, such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Astrocytes exert structural, metabolic and functional effects on neurons, which can be either neurotoxic or neuroprotective. Their neurotoxic effect is mediated via the senescence-associated secretory phenotype (SASP) involving pro-inflammatory cytokines (e.g., IL-6), while their neuroprotective effect is attributed to neurotrophic growth factors (e.g., NGF). We here demonstrate that the p53 isoforms Δ133p53 and p53β are expressed in astrocytes and regulate their toxic and protective effects on neurons. Primary human astrocytes undergoing cellular senescence upon serial passaging in vitro showed diminished expression of Δ133p53 and increased p53β, which were attributed to the autophagic degradation and the SRSF3-mediated alternative RNA splicing, respectively. Early-passage astrocytes with Δ133p53 knockdown or p53β overexpression were induced to show SASP and to exert neurotoxicity in co-culture with neurons. Restored expression of Δ133p53 in near-senescent, otherwise neurotoxic astrocytes conferred them with neuroprotective activity through repression of SASP and induction of neurotrophic growth factors. Brain tissues from AD and ALS patients possessed increased numbers of senescent astrocytes and, like senescent astrocytes in vitro, showed decreased Δ133p53 and increased p53β expression, supporting that our in vitro findings recapitulate in vivo pathology of these neurodegenerative diseases. Our finding that Δ133p53 enhances the neuroprotective function of aged and senescent astrocytes suggests that the p53 isoforms and their regulatory mechanisms are potential targets for therapeutic intervention in neurodegenerative diseases.

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“…6,7 For example, astrocytes isolated from post-mortem human fetal Down syndrome brain were found to be TSP1-deficient. 64 When cocultured with rat hippocampal neurons, they generated altered dendrite lengths, spine malformation and reduced functional synapses that were restored to normal spine morphology and density upon addition of exogenous TSP1.…”

Section: ■ Discussionmentioning

confidence: 99%

Acute and Chronic Mu Opioids Differentially Regulate Thrombospondins 1 and 2 Isoforms in Astrocytes

Phamduong

Rathore

Crews

et al. 2013

ACS Chem. Neurosci.

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Chronic opioids induce synaptic plasticity, a major neuronal adaptation. Astrocyte activation in synaptogenesis may play a critical role in opioid tolerance, withdrawal, and dependence. Thrombospondins 1 and 2 (TSP1/2) are astrocyte-secreted matricellular glycoproteins that promote neurite outgrowth as well as dendritic spine and synapse formation, all of which are inhibited by chronic μ opioids. In prior studies, we discovered that the mechanism of TSP1 regulation by μ opioids in astrocytes involves crosstalk between three different classes of receptors, μ opioid receptor, EGFR and TGFβR. Moreover, TGFβ1 stimulated TSP1 expression via EGFR and ERK/MAPK activation, indicating that EGFR is a signaling hub for opioid and TGFβ1 actions. Using various selective antagonists, and inhibitors, here we compared the mechanisms of chronic opioid regulation of TSP1/2 isoform expression in vivo and in immortalized rat cortical astrocytes. TSP1/2 release from astrocytes was also monitored. Acute and chronic μ opioids, morphine, and the prototypic μ ligand, DAMGO, modulated TSP2 protein levels. TSP2 but not TSP1 protein content was up-regulated by acute (3 h) morphine or DAMGO by an ERK/MAPK dependent mechanism. Paradoxically, TSP2 protein levels were altered neither by TGFβ1 nor by astrocytic neurotrophic factors, EGF, CNTF, and BMP4. TSP1/2 immunofluorescence was increased in astrocytes subjected to scratch-wounding, suggesting TSPs may be useful markers for the "reactive" state of these cells and potentially for different types of injury. Previously, we determined that chronic morphine attenuated both neurite outgrowth and synapse formation in cocultures of primary astrocytes and neurons under similar temporal conditions that μ opioids reduced TSP1 protein levels in astrocytes. Here we found that, after the same 8 day treatment, morphine or DAMGO diminished TSP2 protein levels in astrocytes. Therefore, μ opioids may deter synaptogenesis via both TSP1/2 isoforms, but by distinct mechanisms. KEYWORDS: Opioids, morphine, opioid receptors, astrocytes, ERK/MAPK, growth factors A strocytes make integral contributions to neuronal signaling in the brain by releasing molecules that act at synapses during different stages of synaptogenesis. These phases include pre-and postsynaptic development, function, maintenance, and plasticity.1−7 One family of key astrocyte-secreting molecules includes thrombospondins (TSPs), oligomeric, multidomain glycoproteins that promote synapse formation in vivo and in vitro.8−14 Yet another molecule is TGFβ that induces excitatory synapses at least in part via a D-serine dependent mechanism. 15 Interestingly, TGFβ and TSPs maintain a reciprocal relationship in astrocytes. Early on, it was recognized that TSP1 activates TGFβ. 16 Alternatively, several independent research groups have reported that in astrocytes TGFβ increases TSP1 gene expression and/or protein levels as shown by immunoblotting, qRT-PCR, and in situ hybridization.17−20 Both of these processes appear to be initiated in the extrac...

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Neurological Diseases as Primary Gliopathies: A Reassessment of Neurocentrism

Cited by 223 publications

References 207 publications

Astroglial calcium signalling in Alzheimer's disease

Astroglial calcium signalling in Alzheimer's disease

p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration

Acute and Chronic Mu Opioids Differentially Regulate Thrombospondins 1 and 2 Isoforms in Astrocytes

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