A neuroprotective astrocyte state is induced by neuronal signal EphB1 but fails in ALS models

Tyzack, Giulia E.; Hall, Claire E.; Sibley, Christopher R.; Cymes, Tomasz; Forostyak, Serhiy; Carlino, Giorgio; Meyer, Ione; Schiavo, Giampietro; Zhang, Su‐Chun; Gibbons, George M.; Newcombe, Jia; Patani, Rickie; Lakatos, András

doi:10.1038/s41467-017-01283-z

Cited by 105 publications

(106 citation statements)

References 72 publications

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“…STAT3 signaling in reactive astrocytes has detrimental effects in mouse models of AD (Ceyzériat et al, ; Reichenbach et al, ), or hypoxia (Hristova et al, ), no significant effect in the context of acute mitochondria toxicity (O'Callaghan et al, ) but has beneficial effects in neonatal white matter injury (Nobuta et al, ), after SCI, by promoting glial scar formation (Anderson et al, ; Herrmann et al, ; Okada et al, ), and in HD models, by reducing mutant Huntingtin aggregation (Ben Haim, Ceyzeriat, et al, ). Intriguingly, a recent study by Tyzack et al () suggested that the upstream activator (IL6 or EphB1‐ephrine‐B1 signaling) controls the final molecular profile induced by STAT3 in reactive astrocytes (Table ).…”

Section: Do Reactive Astrocytes Do Good Things?mentioning

confidence: 99%

Questions and (some) answers on reactive astrocytes

Escartin

Guillemaud

Sauvage

2019

Glia

207

180

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Astrocytes are key cellular partners for neurons in the central nervous system. Astrocytes react to virtually all types of pathological alterations in brain homeostasis by significant morphological and molecular changes. This response was classically viewed as stereotypical and is called astrogliosis or astrocyte reactivity. It was long considered as a nonspecific, secondary reaction to pathological conditions, offering no clues on disease‐causing mechanisms and with little therapeutic value. However, many studies over the last 30 years have underlined the crucial and active roles played by astrocytes in physiology, ranging from metabolic support, synapse maturation, and pruning to fine regulation of synaptic transmission. This prompted researchers to explore how these new astrocyte functions were changed in disease, and they reported alterations in many of them (sometimes beneficial, mostly deleterious). More recently, cell‐specific transcriptomics revealed that astrocytes undergo massive changes in gene expression when they become reactive. This observation further stressed that reactive astrocytes may be very different from normal, nonreactive astrocytes and could influence disease outcomes. To make the picture even more complex, both normal and reactive astrocytes were shown to be molecularly and functionally heterogeneous. Very little is known about the specific roles that each subtype of reactive astrocytes may play in different disease contexts. In this review, we have interrogated researchers in the field to identify and discuss points of consensus and controversies about reactive astrocytes, starting with their very name. We then present the emerging knowledge on these cells and future challenges in this field.

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Section: Do Reactive Astrocytes Do Good Things?mentioning

confidence: 99%

Questions and (some) answers on reactive astrocytes

Escartin

Guillemaud

Sauvage

2019

Glia

207

180

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“…Although there is consistent evidence of non-cell autonomous toxicity mediated by astrocytes harboring SOD1 mutations (Ilieva et al, 2009;Marchetto et al, 2008;Nagai et al, 2007;Papadeas et al, 2011;Tripathi et al, 2017;Tyzack et al, 2017), data are either lacking or conflicting for other ALS-related mutations (Haidet-Phillips et al, 2013;Serio et al, 2013;Tong et al, 2013). For example, human iPSCderived astrocytes from a patient harboring an TARDBP M337V mutation did not affect the survival of control iPSC-derived MNs (Serio et al, 2013).…”

Section: Functional Perturbations In C9orf72 Mutantmentioning

confidence: 99%

Mutant C9orf72 human iPSC‐derived astrocytes cause non‐cell autonomous motor neuron pathophysiology

Zhao

Devlin

Chouhan

et al. 2019

Glia

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Mutations in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS). Accumulating evidence implicates astrocytes as important non‐cell autonomous contributors to ALS pathogenesis, although the potential deleterious effects of astrocytes on the function of motor neurons remains to be determined in a completely humanized model of C9orf72‐mediated ALS. Here, we use a human iPSC‐based model to study the cell autonomous and non‐autonomous consequences of mutant C9orf72 expression by astrocytes. We show that mutant astrocytes both recapitulate key aspects of C9orf72‐related ALS pathology and, upon co‐culture, cause motor neurons to undergo a progressive loss of action potential output due to decreases in the magnitude of voltage‐activated Na+ and K+ currents. Importantly, CRISPR/Cas‐9 mediated excision of the C9orf72 repeat expansion reverses these phenotypes, confirming that the C9orf72 mutation is responsible for both cell‐autonomous astrocyte pathology and non‐cell autonomous motor neuron pathophysiology.

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“…For example, inhibiting Stat3 activation in astrocytes in spinal cord injury, where strong astrogliosis contributes to scar formation, worsens outcome (Okada et al, 2006;Herrmann et al, 2008), but has the opposite effect in models of multiple sclerosis (Qin et al, 2012) or neonatal hypoxic brain damage (Hristova et al, 2016). Hence, Stat3 may aggravate or alleviate neurodegeneration in a context-dependent manner (Tyzack et al, 2017), indicating that the full repertoire of cellular pathways initiated by Stat3 signaling remains to be investigated.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Stat3‐mediated astrogliosis ameliorates pathology in an Alzheimer's disease model

et al. 2019

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Reactive astrogliosis is a hallmark of Alzheimer's disease (AD), but its role for disease initiation and progression has remained incompletely understood. We here show that the transcription factor Stat3 (signal transducer and activator of transcription 3), a canonical inducer of astrogliosis, is activated in an AD mouse model and human AD. Therefore, using a conditional knockout approach, we deleted Stat3 specifically in astrocytes in the APP/PS1 model of AD. We found that Stat3‐deficient APP/PS1 mice show decreased β‐amyloid levels and plaque burden. Plaque‐close microglia displayed a more complex morphology, internalized more β‐amyloid, and upregulated amyloid clearance pathways in Stat3‐deficient mice. Moreover, astrocyte‐specific Stat3‐deficient APP/PS1 mice showed decreased pro‐inflammatory cytokine activation and lower dystrophic neurite burden, and were largely protected from cerebral network imbalance. Finally, Stat3 deletion in astrocytes also strongly ameliorated spatial learning and memory decline in APP/PS1 mice. Importantly, these protective effects on network dysfunction and cognition were recapitulated in APP/PS1 mice systemically treated with a preclinical Stat3 inhibitor drug. In summary, our data implicate Stat3‐mediated astrogliosis as an important therapeutic target in AD.

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A neuroprotective astrocyte state is induced by neuronal signal EphB1 but fails in ALS models

Cited by 105 publications

References 72 publications

Questions and (some) answers on reactive astrocytes

Questions and (some) answers on reactive astrocytes

Mutant C9orf72 human iPSC‐derived astrocytes cause non‐cell autonomous motor neuron pathophysiology

Inhibition of Stat3‐mediated astrogliosis ameliorates pathology in an Alzheimer's disease model

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