Cellular Senescence Correlates with Demyelination, Brain Atrophy and Motor Impairment in a Model of Multiple Sclerosis (P2.405)

Objective: To test the hypothesis that demyelination is associated with glial cell senescence Background: Age-related neurodegenerative processes are thought to play a key role in disability progression in MS. Cell senescence (CS) is an age-dependent process, known to promote inflammation and contribute to loss of function associated with aging and neurodegenerative disease. Design/Methods: Demyelination was induced in young (9 week-old), aged (48 week-old) and Terc KO mice (9 week-old), which exhibit accelerated senescence by cuprizone feeding. LFB, MBP, Iba-1, GFAP, APP staining were used to quantify demyelination, microglial/macrophage activation, astrogliosis and axonal damage. Senescent glial cells were detected with senescence-associated β-galactosidase (sen-β-Gal) and lipofuscin histochemistry. The forelimb grip strength test (FLGST) was used for functional assessments. Results: After 16 weeks of cuprizone administration the extent of callosal demyelination did not differ significantly among young, aged and Terc KO mice. Demyelination was less extensive in the aged, compared to the young cuprizone-treated mice after at 4 weeks (P= 0.008), suggesting that ageing is associated with delayed demyelination. Senescent glial cells were significantly increased in the corpus callosum at week 16, compared to controls (P Conclusions: Our study provides evidence of an association of accelerated cellular senescence with demyelination, brain atrophy and motor impairment. Study Supported by: This work is supported by a research grant by the Multiple Sclerosis Trials Collaboration (MSTC), UK Disclosure: Dr. Karamita has nothing to disclose. Dr. Nicholas has nothing to disclose. Dr. Kokoti has nothing to disclose. Dr. Rizou has nothing to disclose. Dr. Mitsikostas has nothing to disclose. Dr. Gorgoulis has nothing to disclose. Dr. Probert has nothing to disclose. Dr. Papadopoulos has nothing to disclose.