Amelioration of Amyotrophic Lateral Sclerosis in SOD1<sup>G93A</sup>Mice by M<sub>2</sub>Microglia from Transplanted Marrow

Epperly, Michael W.; Fisher, Renee; Rigatti, Lora H.; Watkins, Simon C.; Zhang, Xichen; Hou, Wen Chi; Shields, Donna; Franicola, Darcy; Bayır, Hülya; Wang, Hong; Thermozier, Stephanie; Henderson, Andrew J.; Donnelly, Christopher J.; Wipf, Peter; Greenberger, Joel S.

doi:10.21873/invivo.11526

Cited by 4 publications

(4 citation statements)

References 80 publications

(108 reference statements)

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“…However, increased PDGF-C signaling appears to be associated with BSCB disruption in ALS (Liebner et al, 2008), even if PDGFR-α signaling is actually necessary for the survival of these cells (Kisler et al, 2017). Recently, microglial activation, alone or together with peripheral immune cells contribution, has been hypothesized to be involved in the opening of the BSCB (Puentes et al, 2016;Frakes et al, 2017;Epperly et al, 2019). We have demonstrated that chemogenetic control of MN firing can bidirectionally modulate BSCB integrity: Increased firing reduces BSCB disruption, whereas neuronal inactivation worsens it.…”

Section: Discussionmentioning

confidence: 99%

Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

et al. 2020

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Blood–spinal cord barrier (BSCB) disruption is thought to contribute to motoneuron (MN) loss in amyotrophic lateral sclerosis (ALS). It is currently unclear whether impairment of the BSCB is the cause or consequence of MN dysfunction and whether its restoration may be directly beneficial. We revealed that SOD1G93A, FUSΔNLS, TDP43G298S, and Tbk1+/− ALS mouse models commonly shared alterations in the BSCB, unrelated to motoneuron loss. We exploit PSAM/PSEM chemogenetics in SOD1G93A mice to demonstrate that the BSCB is rescued by increased MN firing, whereas inactivation worsens it. Moreover, we use DREADD chemogenetics, alone or in multiplexed form, to show that activation of Gi signaling in astrocytes restores BSCB integrity, independently of MN firing, with no effect on MN disease markers and dissociating them from BSCB disruption. We show that astrocytic levels of the BSCB stabilizers Wnt7a and Wnt5a are decreased in SOD1G93A mice and strongly enhanced by Gi signaling, although further decreased by MN inactivation. Thus, we demonstrate that BSCB impairment follows MN dysfunction in ALS pathogenesis but can be reversed by Gi-induced expression of astrocytic Wnt5a/7a.

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Section: Discussionmentioning

confidence: 99%

Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

et al. 2020

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“…Our results clearly demonstrated that MBP selectively downregulated M1 microglia/macrophage polarization without affecting the increased state of M2 microglia/macrophage polarization in G93A mice even after post-onset administration ( Figure 2 ). Furthermore, it has been reported that M2 microglia/macrophages from transplanted donor marrow delayed onset motor dysfunction in G93A mice [ 36 ]. These results suggest that the ability of MBP to not only maintain the neuroprotective M2 microglia/macrophage polarization but also to prevent the neurotoxic M1 microglia/macrophage polarization could be involved in improving the motor neuron loss and disease progression of G93A mice.…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Effects of Miyako Bidens pilosa in a Mouse Model of Amyotrophic Lateral Sclerosis and Lipopolysaccharide-Stimulated BV-2 Microglia

Tsuruta,

Shidara,

Miyagishi

et al. 2023

IJMS

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Neuroinflammation is a fundamental feature in the pathogenesis of amyotrophic lateral sclerosis (ALS) and arises from the activation of astrocytes and microglial cells. Previously, we reported that Miyako Bidens pilosa extract (MBP) inhibited microglial activation and prolonged the life span in a human ALS-linked mutant superoxide dismutase-1 (SOD1G93A) transgenic mouse model of ALS (G93A mice). Herein, we evaluated the effect of MBP on microglial activation in the spinal cord of G93A mice and lipopolysaccharide-stimulated BV-2 microglial cells. The administration of MBP inhibited the upregulation of the M1-microglia/macrophage marker (interferon-γ receptor (IFN-γR)) and pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6) in G93A mice. However, MBP did not affect the increase in the M2-microglia/macrophage marker (IL-13R) and anti-inflammatory cytokines (transforming growth factor (TGF)-β and IL-10) in G93A mice. BV-2 cell exposure to MBP resulted in a decrease in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) reduction activity and bromodeoxyuridine incorporation, without an increase in the number of ethidium homodimer-1-stained dead cells. Moreover, MBP suppressed the production of lipopolysaccharide-induced pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in BV-2 cells. These results suggest that the selective suppression of M1-related pro-inflammatory cytokines is involved in the therapeutic potential of MBP in ALS model mice.

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“…This effect may be partially explained by the ability of misfolded SOD1 to act as a damage-associated molecular pattern activating TLR receptors [44,45]. SOD1 G93A mice exhibit an improved hematopoiesis compared to mice expressing wild type SOD1, suggesting a specific effect of mutant SOD1 on hematopoietic progenitors [46]. In addition, other factors produced by motor neurons upon damage may potentially induce myeloid and microglial cell attraction and proliferation, including CSF1, MCP1, and ATP, among others [47,48,49,50,51].…”

Section: Discussionmentioning

confidence: 99%

CD34 Identifies a Subset of Proliferating Microglial Cells Associated with Degenerating Motor Neurons in ALS

Kovacs

Trías

Varela

et al. 2019

IJMS

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Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons accompanied by proliferation of reactive microglia in affected regions. However, it is unknown whether the hematopoietic marker CD34 can identify a subpopulation of proliferating microglial cells in the ALS degenerating spinal cord. Immunohistochemistry for CD34 and microglia markers was performed in lumbar spinal cords of ALS rats bearing the SOD1G93A mutation and autopsied ALS and control human subjects. Characterization of CD34-positive cells was also performed in primary cell cultures of the rat spinal cords. CD34 was expressed in a large number of cells that closely interacted with degenerating lumbar spinal cord motor neurons in symptomatic SOD1G93A rats, but not in controls. Most CD34+ cells co-expressed the myeloid marker CD11b, while only a subpopulation was stained for Iba1 or CD68. Notably, CD34+ cells actively proliferated and formed clusters adjacent to damaged motor neurons bearing misfolded SOD1. CD34+ cells were identified in the proximity of motor neurons in autopsied spinal cord from sporadic ALS subjects but not in controls. Cell culture of symptomatic SOD1G93A rat spinal cords yielded a large number of CD34+ cells exclusively in the non-adherent phase, which generated microglia after successive passaging. A yet unrecognized CD34+ cells, expressing or not the microglial marker Iba1, proliferate and accumulate adjacent to degenerating spinal motor neurons, representing an intriguing cell target for approaching ALS pathogenesis and therapeutics.

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Amelioration of Amyotrophic Lateral Sclerosis in SOD1^G93AMice by M₂Microglia from Transplanted Marrow

Cited by 4 publications

References 80 publications

Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

Anti-Inflammatory Effects of Miyako Bidens pilosa in a Mouse Model of Amyotrophic Lateral Sclerosis and Lipopolysaccharide-Stimulated BV-2 Microglia

CD34 Identifies a Subset of Proliferating Microglial Cells Associated with Degenerating Motor Neurons in ALS

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Amelioration of Amyotrophic Lateral Sclerosis in SOD1G93AMice by M2Microglia from Transplanted Marrow

Cited by 4 publications

References 80 publications

Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

Anti-Inflammatory Effects of Miyako Bidens pilosa in a Mouse Model of Amyotrophic Lateral Sclerosis and Lipopolysaccharide-Stimulated BV-2 Microglia

CD34 Identifies a Subset of Proliferating Microglial Cells Associated with Degenerating Motor Neurons in ALS

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Amelioration of Amyotrophic Lateral Sclerosis in SOD1^G93AMice by M₂Microglia from Transplanted Marrow