Abstract
Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS). Histopathological and radiological analysis revealed that neurodegeneration occurs early in the disease course. However, the pathological mechanisms involved in neurodegeneration are poorly understood. Myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in Brown Norway rats (BN-rats) is a well-established animal model, especially of the neurodegenerative aspects of MS. Previous studies in this animal model indicated that loss of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve, occurs in the preclinical phase of the disease and is in part independent of overt histopathological changes of the optic nerve. Therefore, the aim of this study was to identify genes which are involved in neuronal cell loss at different disease stages of EAE. Furthermore, genes that are highly specific for autoimmune-driven neurodegeneration were compared to those regulated in RGCs after optic nerve axotomy at corresponding time points. Using laser capture micro dissection we isolated RNA from unfixed RGCs and performed global transcriptome analysis of retinal neurons. In total, we detected 582 genes sequentially expressed in the preclinical phase and 1150 genes in the clinical manifest EAE (P < 0.05, fold-induction >1.5). Furthermore, using ingenuity pathway analysis (IPA), we identified amyloid precursor protein (APP) as a potential upstream regulator of changes in gene expression in the preclinical EAE but neither in clinical EAE, nor at any time point after optic nerve transection. Therefore, the gene pathway analysis lead to the hypothesis that altered cleavage of APP in neurons in the preclinical phase of EAE leads to the enhanced production of APP intracellular domain (AICD), which in turn acts as a transcriptional regulator and thereby initiates an apoptotic signaling cascade via up-regulation of the target gene p53.
Highlights
Multiple Sclerosis (MS) is generally described as a chronic autoimmune demyelinating disease of the central nervous system in which immune attack by T- and B-cells against myelin sheath leads to focal lesions in the CNS and subsequent neuronal damage [1]
We used an active EAE-model in Brown Norway (BN) rats based on immunization with recombinant myelin oligodendrocyte glycoprotein (MOG)
Using a 1.5 fold-induction and a false discovery rate of 5%, we detected 582 genes sequentially regulated in the preclinical phase of EAE (MOG_7dpi) and 1053 seven days after optic nerve transection (ONT_7)
Summary
Multiple Sclerosis (MS) is generally described as a chronic autoimmune demyelinating disease of the central nervous system in which immune attack by T- and B-cells against myelin sheath leads to focal lesions in the CNS and subsequent neuronal damage [1]. We used an active EAE-model in Brown Norway (BN) rats based on immunization with recombinant myelin oligodendrocyte glycoprotein (MOG). This animal model mimics several aspects of the human disease, including the contribution of B- and T-cells to the inflammation, demyelination and cell death [7]. Making it more likely that gene-expression changes in neurons are involved in neurodegeneration under autoimmune conditions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
