Multiple sclerosis (MS) is an autoimmune and neurodegenerative disorder of the central nervous system (CNS), a heterogeneous disease that courses with both demyelination and inflammation. We used two different animal models to recapitulate different aspects of this disease, experimental autoimmune encephalomyelitis (EAE) and cuprizone (CPZ) induced demyelination. To study the differential response of the CNS, we compared the proteomic profile of EAE mice (at peak disease) and CPZ mice (in the acute phase) in two different CNS regions: somatosensorial cortex (Cx) and spinal cord (SC). Our results show a diverse regional glial response in each MS model, identifying only one common protein altered in both models and regions, Orosomucoid-1 (Orm1), also referred to as Alpha-1-acid glycoprotein 1 (AGP1). Here, we describe the alterations to Orm1 in the cortex of EAE and CPZ mice for the first time, and its presence in the brain of human RRMS patients, reflecting on the significance of these changes in MS.