In vivo imaging reveals rapid morphological reactions of astrocytes towards focal lesions in an ALS mouse model

Dibaj, Payam; Steffens, Heinz; Zschüntzsch, Jana; Kirchhoff, Frank; Schomburg, E. D.; Neusch, Clemens

doi:10.1016/j.neulet.2011.04.049

Cited by 20 publications

(17 citation statements)

References 21 publications

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“…Microglia were revealed to aggregate, proliferate, and phagocyte in the lumbar SC of pre-symptomatic mutant SOD1H46R transgenic mice (Sanagi et al, 2010). However, in other studies microglia have shown to contribute to MN death (Dibaj et al, 2011; Brettschneider et al, 2012) and to decrease in number within disease progression (Butovsky et al, 2012), thus contributing to the disease propagation. By using in vivo imaging by two-photon laser-scanning microscopy and axonal transection, it was observed different phases of microglia-mediated inflammation in the ALS mice model.…”

Section: Neurodegenerative Networking In Alsmentioning

confidence: 95%

“…By using in vivo imaging by two-photon laser-scanning microscopy and axonal transection, it was observed different phases of microglia-mediated inflammation in the ALS mice model. Indeed, a first phase (preclinical) with highly reactive microglia was followed by another (clinical stage) with morphologically transformed microglia presenting reduced surveillance activity and reactivity (Dibaj et al, 2011). Regional, temporal, and immune environmental differences may contribute to changes in microglia phenotypes and response heterogeneity, thus requiring differentiated immunomodulatory or even combinatory therapeutic approaches along ALS disease progression.…”

Section: Neurodegenerative Networking In Alsmentioning

confidence: 99%

“…Recent data obtained in the mSOD1 mouse model suggest a dominant neuroinflammatory response in the CNS, with a reactive microglia in preclinical stages that turns into an irresponsive cell during disease progression, and a degenerative process in the PNS (Dibaj et al, 2011). Earlier studies evidenced that mutated SOD1 microglia have an age-dependent cytotoxic potential which reveals upon a stimulatory effect (Weydt et al, 2004).…”

Section: Challenges To Nerve Regeneration In Alsmentioning

confidence: 99%

“…Indeed, the neurodegenerative process in ALS was shown to be accompanied by a sustained inflammation in the brain and spinal cord (SC) (Bowerman et al, 2013). Recently, microglia were suggested to be implicated in ALS initiation (Gerber et al, 2012), as well as to lose their surveillance capacity by switching from an activated to a neurodegenerative phenotype as the disease progresses (Weydt et al, 2004; Dibaj et al, 2011). Therefore, a better therapeutic strategy should envisage the recovery of healthy microglia from those transformed cells near the most affected MNs in the SC.…”

Section: Introductionmentioning

confidence: 99%

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Microglia centered pathogenesis in ALS: insights in cell interconnectivity

Brites

Vaz

2014

Front. Cell. Neurosci.

176

137

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Amyotrophic lateral sclerosis (ALS) is the most common and most aggressive form of adult motor neuron (MN) degeneration. The cause of the disease is still unknown, but some protein mutations have been linked to the pathological process. Loss of upper and lower MNs results in progressive muscle paralysis and ultimately death due to respiratory failure. Although initially thought to derive from the selective loss of MNs, the pathogenic concept of non-cell-autonomous disease has come to the forefront for the contribution of glial cells in ALS, in particular microglia. Recent studies suggest that microglia may have a protective effect on MN in an early stage. Conversely, activated microglia contribute and enhance MN death by secreting neurotoxic factors, and impaired microglial function at the end-stage may instead accelerate disease progression. However, the nature of microglial–neuronal interactions that lead to MN degeneration remains elusive. We review the contribution of the neurodegenerative network in ALS pathology, with a special focus on each glial cell type from data obtained in the transgenic SOD1G93A rodents, the most widely used model. We further discuss the diverse roles of neuroinflammation and microglia phenotypes in the modulation of ALS pathology. We provide information on the processes associated with dysfunctional cell–cell communication and summarize findings on pathological cross-talk between neurons and astroglia, and neurons and microglia, as well as on the spread of pathogenic factors. We also highlight the relevance of neurovascular disruption and exosome trafficking to ALS pathology. The harmful and beneficial influences of NG2 cells, oligodendrocytes and Schwann cells will be discussed as well. Insights into the complex intercellular perturbations underlying ALS, including target identification, will enhance our efforts to develop effective therapeutic approaches for preventing or reversing symptomatic progression of this devastating disease.

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Section: Neurodegenerative Networking In Alsmentioning

confidence: 95%

Section: Neurodegenerative Networking In Alsmentioning

confidence: 99%

Section: Challenges To Nerve Regeneration In Alsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Microglia centered pathogenesis in ALS: insights in cell interconnectivity

Brites

Vaz

2014

Front. Cell. Neurosci.

176

137

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“…Over-expression of mutant human SOD1 in animal models results in motor neuron disease. Some studies suggest that this pathology is driven by a non-cell autonomous toxicity mediated by astrocytes, neurons or microglia (Boillee et al 2006a; Dibaj et al 2011; Ilieva et al 2009). …”

Section: Introductionmentioning

confidence: 99%

Spinal but not cortical microglia acquire an atypical phenotype with high VEGF, galectin-3 and osteopontin, and blunted inflammatory responses in ALS rats

Nikodémová

Small

Smith

et al. 2014

Neurobiology of Disease

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Activation of microglia, CNS resident immune cells, is a pathological hallmark of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting motor neurons. Despite evidence that microglia contribute to disease progression, the exact role of these cells in ALS pathology remains unknown. We immunomagnetically isolated microglia from different CNS regions of SOD1G93A rats at three different points in disease progression: presymptomatic, symptom onset and end-stage. We observed no differences in microglial number or phenotype in presymptomatic rats compared to wild-type controls. Although after disease onset there was no macrophage infiltration, there were significant increases in microglial numbers in the spinal cord, but not cortex. At disease end-stage, microglia were characterized by high expression of galectin-3, osteopontin and VEGF, and concomitant downregulated expression of TNFα, IL-6, BDNF and arginase-1. Flow cytometry revealed the presence of at least two phenotypically distinct microglial populations in the spinal cord. Immunohistochemistry showed that galectin-3/osteopontin positive microglia were restricted to the ventral horns of the spinal cord, regions with severe motor neuron degeneration. End-stage SOD1G93A microglia from the cortex, a less affected region, displayed similar gene expression profiles to microglia from wild-type rats, and displayed normal responses to systemic inflammation induced by LPS. On the other hand, end-stage SOD1G93A spinal microglia had blunted responses to systemic LPS suggesting that in addition to their phenotypic changes, they may also be functionally impaired. Thus, after disease onset, microglia acquired unique characteristics that do not conform to typical M1 (inflammatory) or M2 (anti-inflammatory) phenotypes. This transformation was observed only in the most affected CNS regions, suggesting that overexpression of mutated hSOD1 is not sufficient to trigger these changes in microglia. These novel observations suggest that microglial regional and phenotypic heterogeneity may be an important consideration when designing new therapeutic strategies targeting microglia and neuroinflammation in ALS.

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Optical Imaging of the Spinal Cord for the Study of Pain: From Molecules to Neural Networks

Chisholm

McMahon

2022

Neuromethods

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In vivo imaging reveals rapid morphological reactions of astrocytes towards focal lesions in an ALS mouse model

Cited by 20 publications

References 21 publications

Microglia centered pathogenesis in ALS: insights in cell interconnectivity

Microglia centered pathogenesis in ALS: insights in cell interconnectivity

Spinal but not cortical microglia acquire an atypical phenotype with high VEGF, galectin-3 and osteopontin, and blunted inflammatory responses in ALS rats

Optical Imaging of the Spinal Cord for the Study of Pain: From Molecules to Neural Networks

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