Therapeutic opportunities for targeting cellular senescence in progressive multiple sclerosis

Sutter, Pearl A.; McKenna, Mark G; Imitola, Jaime; Pijewski, Robert S; Crocker, Stephen J.

doi:10.1016/j.coph.2022.102184

Cited by 2 publications

(2 citation statements)

References 63 publications

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“…Indeed, BTK inhibitors may decrease expression of proinflammatory cytokines including TNF, overexpression of which is associated with the proinflammatory, senescent transcriptomic profile seen here in EAE microglia 44 . Targeting microglia is particularly relevant in the case of progressive MS, for which few therapies are currently available and effective at preventing CNS degeneration occurring independent of inflammatory relapses 45 . In MS, reactive microglia particularly contribute to the pathology of chronic active lesions, which are associated with heightened disease progression in patients 3,26,46 .…”

Section: Discussionmentioning

confidence: 99%

Senolytic treatment depletes microglia and decreases severity of experimental autoimmune encephalomyelitis

Drake,

Zaman,

Gianfelice

et al. 2024

Preprint

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The role of senescence in disease contexts is complex, however there is considerable evidence that depletion of senescent cells improves outcomes in a variety of contexts particularly related to aging, cognition, and neurodegeneration. Here, the effect of a bioinformatically-rationalized senolytic was tested in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis (MS). Single-cell analysis from brain tissue isolated from mice subjected to EAE identified microglia with a strong senescence signature including the presence of BCL2-family member transcripts. Cells expressing Bcl2l1 had higher expression of pro-inflammatory and senescence genes than their negative counterparts in EAE, suggesting they may exacerbate inflammation. Notably, in human single-nucleus sequencing from MS, BCL2L1 positive microglia were strongly enriched in lesions with active inflammatory pathology, and likewise demonstrated increased expression of immune related genes suggesting they may contribute to the active lesion pathology and tissue damage in chronic active lesions. Employing a small molecule BCL2 inhibitor, Navitoclax (ABT-263), significantly reduced the presence of microglia in the EAE spinal cord, suggesting that these cells can be targeted by senolytic treatment. ABT-263 treatment had a profound effect on EAE mice, decreasing motor symptom severity, improving visual acuity, promoting neuronal survival, and decreasing white matter inflammation. Together, these results provide evidence to support the idea that senescent glia may exacerbate inflammation resulting in negative outcomes in neuroinflammatory disease and that removing them may ameliorate disease.

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Section: Discussionmentioning

confidence: 99%

Senolytic treatment depletes microglia and decreases severity of experimental autoimmune encephalomyelitis

Drake,

Zaman,

Gianfelice

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Indeed, there is evidence of biomarkers of accelerated aging of the immune system, like shortened telomeres, that may contribute to the progressive decline in health experienced by older MS patients 45 . Thus, there remain many considerations and avenues for investigation into aging and senescence as a therapeutic target in the CNS in disease, particularly for MS. New approaches incorporating existing immunomodulatory agents, in combination with novel anti-senescence and promyelinating therapeutics may be key to promoting long term health of patients in the future 46,47 .…”

Section: Discussionmentioning

confidence: 99%

Cellular rejuvenation protects neurons from inflammation mediated cell death

Drake,

Mohammadnia,

Heale

et al. 2023

Preprint

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In multiple sclerosis (MS), the invasion of the central nervous system by peripheral immune cells is followed by the activation of resident microglia and astrocytes. This cascade of events results in demyelination, which triggers neuronal damage and death. The molecular signals in neurons responsible for this damage are not yet fully characterized. In MS, retinal ganglion cell neurons (RGCs) of the central nervous system (CNS) undergo axonal injury and cell death. This phenomenon is mirrored in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. To understand the molecular landscape, we isolated RGCs from mice subjected to the EAE protocol. RNA-sequencing and ATAC-sequencing analyses were performed. Pathway analysis of the RNA-sequencing data revealed that RGCs displayed a molecular signature, similar to aged neurons, showcasing features of senescence. Single-nucleus RNA-sequencing analysis of neurons from human MS patients revealed a comparable senescence-like phenotype., which was supported by immunostaining RGCs in EAE mice. These changes include alterations to the nuclear envelope, modifications in chromatin marks, and accumulation of DNA damage. Transduction of RGCs with anOct4-Sox2-Klf4transgene to convert neurons in the EAE model to a more youthful epigenetic and transcriptomic state enhanced the survival of RGCs. Collectively, this research uncovers a previously unidentified senescent-like phenotype in neurons under pathological inflammation and neurons from MS patients. The rejuvenation of this aged transcriptome improved visual acuity and neuronal survival in the EAE model supporting the idea that age rejuvenation therapies and senotherapeutic agents could offer a direct means of neuroprotection in autoimmune disorders.

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Therapeutic opportunities for targeting cellular senescence in progressive multiple sclerosis

Cited by 2 publications

References 63 publications

Senolytic treatment depletes microglia and decreases severity of experimental autoimmune encephalomyelitis

Senolytic treatment depletes microglia and decreases severity of experimental autoimmune encephalomyelitis

Cellular rejuvenation protects neurons from inflammation mediated cell death

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