042 – Inhibition of cellular senescence with low-dose rapamycin has beneficial effects on myelin repair and neuroprotection in a model of multiple sclerosis
Maria Avloniti (1) – Irini Papazian (1) – Maria Karamita (1) – Richard Nicholas (2) – Lesley Probert (1) – Dimitris Papadopoulos (1)
Hellenic Pasteur Institute, Molecular Genetics, Athens, Greece (1) – Imperial college of London, Department of Medicine, London, United Kingdom (2)
Cell senescence (CS) is an age-dependent process, known to be accelerated by chronic inflammation. CS is thought to prevent damaged cells from becoming neoplastic, but accelerated CS also contributes to loss of function associated with aging and neurodegenerative disease. To investigate whether chronic CNS inflammation and demyelination promotes CS in the brain we administered dietary cuprizone (CPZ) (0.2% w/w) to groups of young (9 week-old) and aged (48 week-old) mice for 16 weeks, followed by 4 weeks normal diet, and measured effects on development of neuropathology, motor function and presence of CS markers. Neuropathological analysis showed that CPZ induced extensive demyelination (anti-MBP) in corpus callosum (cc) of young and aged mice. Quantification of demyelination in midline cc revealed less demyelination in aged compared to young mice after 4 weeks of cuprizone feeding (CPZ4)(P= 0.008), but equal levels at CPZ8 or CPZ16, indicating that aged mice are more resistant to CPZ demyelination. Similarly, CPZ-induced astrogliosis (anti-GFAP), microgliosis (anti-Iba-1) and axonal damage (anti-APP) were delayed in aged compared to young mice. Interestingly, similar to an acute 6-week CPZ model, in this chronic model there was efficient myelin recovery and absence of acute axon damage at 4 weeks following withdrawal of CPZ from the diet (CPZ16+4), suggesting that the cc retains remyelination potential. Histopathological changes in young CPZ mice were associated with increased DAPI autofluorescence, a marker of senescence, in cc glial cells and in M1 cortical cells, compared to nave age-matched controls. CPZ-treated mice developed brain atrophy as brain weights were 8% lower than those in nave controls at CPZ16 (P<0,001). Young CPZ-treated mice showed reduced motor function, detected from CPZ5 onwards using the rotarod test and at CPZ16 using the grip strength, compared to nave controls. Univariate logistic regression revealed that age (P< 0.0001), demyelination (P< 0.014), and time from onset of CPZ feeding (P< 000.1) all correlated significantly with latency to fall off the rotarod. To further investigate whether axonal damage and motor impairment in chronic demyelinating disease are associated with CS we tested the effects of low-dose treatment with rapamycin, an inhibitor of mTOR that inhibits CS in vitro, on the development of neuropathology in young CPZ-treated mice. Quantitative neuropathological analysis showed that rapamycin administration reduced astrogliosis (week 8), allowed early recovery of myelin (week 16), reduced axon damage (week 16), and increased motor function, compared to non-treated CPZ mice, suggesting that inhibition of CS has beneficial effects on remyelination and neuroprotection in this model. Further investigations are currently underway to identify the cell specificity of CS in aged and demyelinating brain using this model of multiple sclerosis.