Contributions
Abstract: EP1509
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 19 Neurodegeneration
Background: Cell senescence (CS) is an age-dependent process, promoted by a number of factors including oxidative stress and chronic inflammation. Typically, senescent cells undergo a number of changes such as division arrest and pro-inflammatory cytokine production. CS is thought to prevent damaged cells from becoming neoplastic, but evidence suggests that accelerated CS also contributes to loss of function associated with aging and neurodegenerative disease. The mechanisms that drive disability in the progressive forms of MS are not fully understood but age-related neurodegenerative processes are thought to play a key role.
Aim: To test the hypothesis that axonal damage and motor impairment in chronic demyelinating disease are associated with glial cell senescence.
Methods: We used the cuprizone model of demyelination in C57BL/6 mice. Immunohistochemistry for MBP, Iba-1 GFAP, APP were used to quantify demyelination, microglial/macrophage activation, astrogliosis and acute axonal damage, respectively. γH2AX was used as a marker of DNA damage response (DDR). Senescent glial cells were detected with senescence-associated β-galactosidase (SA-β-Gal) histochemistry and p16INK4A immunohistochemistry. The rotarod test and four-limb grip strength were used to assess motor performance.
Results: Chronic cuprizone feeding for 16 weeks led to callosal demyelination and astrogliosis with extensive acute axonal damage. In the corpus callosum of cuprizone-treated, but not naïve mice, γH2AX immunohistochemistry was present in glial cell nuclei. There was also a significant increase in SA-β-Gal and P16INK4A positive senescent glial cells in the corpus callosum, compared to naïve controls (P< 0.001 and P< 0.05, respectively). Brain atrophy in cuprizone-treated mice was attested by decreased brain weight (8%, P< 0.001), and performance using the rotarod test and four-limb grip strength (P< 0.01), compared to naïve controls. Correlation analysis revealed a significant association between the senescent glial cell load and four-limb grip strength (rp= -0.867, P< 0.01), and between the senescent glial cell load and the extent of acute axonal damage (rp= 0.92, P< 0.01).
Conclusions: Our study provides evidence of an association of axonal damage and motor impairment with the extent of glial cell senescence in a model of chronic demyelination. These data indicate that glial cell senescence might contribute to disability progression under conditions of chronic demyelination.
Disclosure: This work is supported by a research grant by the Multiple Sclerosis Trials Collaboration (MSTC), UK
Dr Papadopoulos D reports honoraria, travel grants and consultation fees from Novartis, Bayer, Teva, Sanofi-Genzyme, Genesis Pharma, Roche and Merck-Serono.
Dr Karamita M: nothing to disclose
Dr Mitsikostas DD reports honoraria, travel grants and consultation fees from Novartis, Sanofi-Genzyme, Genesis Pharma, Merck-Serono, Teva and research grants from Merck-Serono and Genesis Pharma.
Professor Gorgoulis V: nothing to disclose
Dr Probert L: nothing to disclose
Dr Nicholas R: honoraria, travel grants and consultation fees from Novartis, Sanofi-Genzyme, Biogen and Roche.
Abstract: EP1509
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 19 Neurodegeneration
Background: Cell senescence (CS) is an age-dependent process, promoted by a number of factors including oxidative stress and chronic inflammation. Typically, senescent cells undergo a number of changes such as division arrest and pro-inflammatory cytokine production. CS is thought to prevent damaged cells from becoming neoplastic, but evidence suggests that accelerated CS also contributes to loss of function associated with aging and neurodegenerative disease. The mechanisms that drive disability in the progressive forms of MS are not fully understood but age-related neurodegenerative processes are thought to play a key role.
Aim: To test the hypothesis that axonal damage and motor impairment in chronic demyelinating disease are associated with glial cell senescence.
Methods: We used the cuprizone model of demyelination in C57BL/6 mice. Immunohistochemistry for MBP, Iba-1 GFAP, APP were used to quantify demyelination, microglial/macrophage activation, astrogliosis and acute axonal damage, respectively. γH2AX was used as a marker of DNA damage response (DDR). Senescent glial cells were detected with senescence-associated β-galactosidase (SA-β-Gal) histochemistry and p16INK4A immunohistochemistry. The rotarod test and four-limb grip strength were used to assess motor performance.
Results: Chronic cuprizone feeding for 16 weeks led to callosal demyelination and astrogliosis with extensive acute axonal damage. In the corpus callosum of cuprizone-treated, but not naïve mice, γH2AX immunohistochemistry was present in glial cell nuclei. There was also a significant increase in SA-β-Gal and P16INK4A positive senescent glial cells in the corpus callosum, compared to naïve controls (P< 0.001 and P< 0.05, respectively). Brain atrophy in cuprizone-treated mice was attested by decreased brain weight (8%, P< 0.001), and performance using the rotarod test and four-limb grip strength (P< 0.01), compared to naïve controls. Correlation analysis revealed a significant association between the senescent glial cell load and four-limb grip strength (rp= -0.867, P< 0.01), and between the senescent glial cell load and the extent of acute axonal damage (rp= 0.92, P< 0.01).
Conclusions: Our study provides evidence of an association of axonal damage and motor impairment with the extent of glial cell senescence in a model of chronic demyelination. These data indicate that glial cell senescence might contribute to disability progression under conditions of chronic demyelination.
Disclosure: This work is supported by a research grant by the Multiple Sclerosis Trials Collaboration (MSTC), UK
Dr Papadopoulos D reports honoraria, travel grants and consultation fees from Novartis, Bayer, Teva, Sanofi-Genzyme, Genesis Pharma, Roche and Merck-Serono.
Dr Karamita M: nothing to disclose
Dr Mitsikostas DD reports honoraria, travel grants and consultation fees from Novartis, Sanofi-Genzyme, Genesis Pharma, Merck-Serono, Teva and research grants from Merck-Serono and Genesis Pharma.
Professor Gorgoulis V: nothing to disclose
Dr Probert L: nothing to disclose
Dr Nicholas R: honoraria, travel grants and consultation fees from Novartis, Sanofi-Genzyme, Biogen and Roche.