Lumbar spinal cord microglia exhibited increased activation in aging dogs compared with young adult dogs

Toedebusch, Christine M.; Garcia, Virginia B.; Snyder, John C.; Jones, Maria R.; Schulz, David J.; Johnson, Gayle C.; Villalón, Eric; Coates, Joan R.; Garcia, Michael L.

doi:10.1007/s11357-019-00133-8

Cited by 8 publications

(6 citation statements)

References 56 publications

(79 reference statements)

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“…Our finding that microglia tiling was disrupted with age primarily in the ventral horn led us to suspect that these microglia were migrating to a specific subregion of the ventral horn, as they respond to some type of stimulus. Our analysis of microglia‐neuronal interactions revealed an obvious association between aged microglia lacking a ramified morphology and motor neurons, which has been alluded to previously in aged canines (Toedebusch et al, 2020). Importantly, recent evidence has also linked microglia accumulation in the ventral horn to the degeneration of motor neurons in aged humans (Buchman et al, 2019).…”

Section: Discussionsupporting

confidence: 74%

“…Contact was defined as direct apposition or overlap of the GFP and NeuN signal regardless of the location of this contact on either cell. We focused on the lumbar spinal cord region because motor neurons in this region display increased susceptibility to age‐related degeneration as compared to more rostrally located regions (Mayhew et al, 2020; Toedebusch et al, 2020). We found that individual neurons in the DH, IG, and VH were contacted by a similar number of microglia in young adult mice (Figure 4c).…”

Section: Resultsmentioning

confidence: 99%

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Aging spinal cord microglia become phenotypically heterogeneous and preferentially target motor neurons and their synapses

Castro,

Lopes,

De Biase

et al. 2023

Glia

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Microglia have been found to acquire unique region‐dependent deleterious features with age and diseases that contribute to neuronal dysfunction and degeneration in the brain. However, it remains unknown whether microglia exhibit similar phenotypic heterogeneity in the spinal cord. Here, we performed a regional analysis of spinal cord microglia in 3‐, 16‐, 23‐, and 30‐month‐old mice. Using light and electron microscopy, we discovered that spinal cord microglia acquire an increasingly activated phenotype during the course of aging regardless of regional location. However, aging causes microglia in the ventral but not dorsal horn to lose their spatial organization. Aged ventral horn microglia also aggregate around the somata of motor neurons and increase their contacts with motor synapses, which have been shown to be lost with age. These findings suggest that microglia may affect the ability of motor neurons to receive and relay motor commands during aging. To generate additional insights about aging spinal cord microglia, we performed RNA‐sequencing on FACS‐isolated microglia from 3‐, 18‐, 22‐, and 29‐month‐old mice. We found that spinal cord microglia acquire a similar transcriptional identity as those in the brain during aging that includes altered expression of genes with roles in microglia‐neuron interactions and inflammation. By 29 months of age, spinal cord microglia exhibit additional and unique transcriptional changes known and predicted to cause senescence and to alter lysosomal and ribosomal regulation. Altogether, this work provides the foundation to target microglia to ameliorate aged‐related changes in the spinal cord, and particularly on the motor circuit.

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Section: Discussionsupporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Aging spinal cord microglia become phenotypically heterogeneous and preferentially target motor neurons and their synapses

Castro,

Lopes,

De Biase

et al. 2023

Glia

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“…Morphometric analysis of intratumoral Iba-1+ cells revealed that normal canine brain demonstrated the homogeneous distribution of Iba-1+ cells with a small cell body and several branched processes, consistent with a ramified morphology ( Figure 2A ). 27 Conversely, GAM morphology across tumor grades reflected a larger cellular population lacking the typical ramified morphology ( Figure 2 ). Compared to normal cortical microglia, the total GAM area was increased in grade III astrocytomas (551 ± 103 vs 279 ± 25; P < .05; Figure 2A and B ).…”

Section: Resultsmentioning

confidence: 99%

Glioma-associated microglia/macrophages augment tumorigenicity in canine astrocytoma, a naturally occurring model of human glioma

Toedebusch

Grodzki

Dickinson

et al. 2021

Neuro-Oncology Advances

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Background Glioma-associated microglia/macrophage (GAM) markedly influence glioma progression. Under the influence of transforming growth factor beta (TGFB), GAM are polarized toward a tumor-supportive phenotype. However, neither therapeutic targeting of GAM recruitment, nor TGF Beta (TGFB) signaling demonstrated efficacy in glioma patients despite efficacy in preclinical models, underscoring the need for a comprehensive understanding of the TGFB/GAM axis. Spontaneously occurring canine gliomas share many features with human glioma and provide a complementary translational animal model for further study. Given the importance of GAM and TGFB in human glioma, the aims of this study were to further define the GAM-associated molecular profile and the relevance of TGFB signaling in canine glioma that may serve as the basis for future translational studies. Methods GAM morphometry, levels of GAM-associated molecules, and the canonical TGFB signaling axis were compared in archived samples of canine astrocytomas versus normal canine brain. Further, the effect of TGFB on the malignant phenotype of canine astrocytoma cells was evaluated. Results GAMs diffusely infiltrated canine astrocytomas. GAM density was increased in high-grade tumors that correlated with a pro-tumorigenic molecular signature and up-regulation of the canonical TGFB signaling axis. Moreover, TGFB1 enhanced migration of canine astrocytoma cells in vitro. Conclusions Canine astrocytomas share a similar GAM-associated immune landscape with human adult glioma. Our data also support a contributing role for TGFB1 signaling in the malignant phenotype of canine astrocytoma. These data further support naturally occurring canine glioma as a valid model for investigation of GAM-associated therapeutic strategies for human malignant glioma.

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“…The existing literature, as well as our study, support the presence of both para-inflammatory state and demyelination in the aging spinal cord. Moreover, a recent study by Toedebusch et al (2019) reports microglia polarization toward a pro-inflammatory phenotype preferentially in the lumbar spinal cord of aging dogs. The reported "primed" state of the microglia corresponds to microglia activation without pronounced cytokine release, similar to what we observed in this study.…”

Section: Discussionmentioning

confidence: 96%

Molecular changes associated with spinal cord aging

et al. 2020

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Age-related muscle weakness and loss of muscle mass (sarcopenia) is a universal problem in the elderly. Our previous studies indicate that alpha motor neurons (α-MNs) play a critical role in this process. The goal of the current study is to uncover changes in the aging spinal cord that contribute to loss of innervation and the downstream degenerative processes that occur in skeletal muscle. The number of α-MNs is decreased in the spinal cord of wildtype mice during aging, beginning in middle age and reaching a 41% loss by 27 months of age. There is evidence for age-related loss of myelin and mild inflammation, including astrocyte and microglia activation and an increase in levels of sICAM-1. We identified changes in metabolites consistent with compromised neuronal viability, such as reduced levels of N-acetyl-aspartate. Cleaved caspase-3 is more abundant in spinal cord from old mice, suggesting that apoptosis contributes to neuronal loss. RNA-seq analysis revealed changes in the expression of a number of genes in spinal cord from old mice, in particular genes encoding extracellular matrix components (ECM) and a 172-fold increase in MMP-12 expression. Furthermore, blood-spinal cord barrier (BSCB) permeability is increased in old mice, which may contribute to alterations in spinal cord homeostasis and exacerbate neuronal distress. Together, these data show for the first time that the spinal cord undergoes significant changes during aging, including progressive α-MNs loss that is associated with low-grade inflammation, apoptosis, changes in ECM, myelination, and vascular permeability.

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Lumbar spinal cord microglia exhibited increased activation in aging dogs compared with young adult dogs

Cited by 8 publications

References 56 publications

Aging spinal cord microglia become phenotypically heterogeneous and preferentially target motor neurons and their synapses

Aging spinal cord microglia become phenotypically heterogeneous and preferentially target motor neurons and their synapses

Glioma-associated microglia/macrophages augment tumorigenicity in canine astrocytoma, a naturally occurring model of human glioma

Molecular changes associated with spinal cord aging

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