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Neurodegeneration in Autoimmune Optic Neuritis Is Associated with Altered APP Cleavage in Neurons and Up-Regulation of p53.

Herold S, Kumar P, Wichert SP, Kretzschmar B, Bähr M, Rossner MJ, Hein K - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University Medicine Göttingen, Göttingen, Germany.

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.

No MeSH data available.


Related in: MedlinePlus

Cell death and survival pathways associated with APP in EAE and optic nerve transection (ONT):(A) connection of upstream regulator APP in whole dataset of preclinical EAE (MOG_7dpi), (B) set of genes that are commonly regulated in MOG_7dpi and in ONT_7 in the same direction, (C) indicate APP-connected genes specific for MOG_7dpi specific genes after subtraction of ONT_7 genes. APP-responsive genes at day of clinical manifestation of the disease (d1EAE) (D) and in ONT_14 (E). Pointed arrowheads represent activating relationships, dashed lines indicate indirect activation and solid lines direct activation. Red lines point to genes in the network that are involved in the biological processes “neural apoptosis” or “immune response.
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pone.0138852.g002: Cell death and survival pathways associated with APP in EAE and optic nerve transection (ONT):(A) connection of upstream regulator APP in whole dataset of preclinical EAE (MOG_7dpi), (B) set of genes that are commonly regulated in MOG_7dpi and in ONT_7 in the same direction, (C) indicate APP-connected genes specific for MOG_7dpi specific genes after subtraction of ONT_7 genes. APP-responsive genes at day of clinical manifestation of the disease (d1EAE) (D) and in ONT_14 (E). Pointed arrowheads represent activating relationships, dashed lines indicate indirect activation and solid lines direct activation. Red lines point to genes in the network that are involved in the biological processes “neural apoptosis” or “immune response.

Mentions: Comparison of APP-responsive gene set in preclinical EAE (MOG_7dpi) with sequentially regulated genes in clinical manifest EAE (d1EAE) as well as/or in ONT revealed that APP-dependent gene-regulation seems to be a specific phenomenon for the early phase of EAE (Fig 2).


Neurodegeneration in Autoimmune Optic Neuritis Is Associated with Altered APP Cleavage in Neurons and Up-Regulation of p53.

Herold S, Kumar P, Wichert SP, Kretzschmar B, Bähr M, Rossner MJ, Hein K - PLoS ONE (2015)

Cell death and survival pathways associated with APP in EAE and optic nerve transection (ONT):(A) connection of upstream regulator APP in whole dataset of preclinical EAE (MOG_7dpi), (B) set of genes that are commonly regulated in MOG_7dpi and in ONT_7 in the same direction, (C) indicate APP-connected genes specific for MOG_7dpi specific genes after subtraction of ONT_7 genes. APP-responsive genes at day of clinical manifestation of the disease (d1EAE) (D) and in ONT_14 (E). Pointed arrowheads represent activating relationships, dashed lines indicate indirect activation and solid lines direct activation. Red lines point to genes in the network that are involved in the biological processes “neural apoptosis” or “immune response.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4591258&req=5

pone.0138852.g002: Cell death and survival pathways associated with APP in EAE and optic nerve transection (ONT):(A) connection of upstream regulator APP in whole dataset of preclinical EAE (MOG_7dpi), (B) set of genes that are commonly regulated in MOG_7dpi and in ONT_7 in the same direction, (C) indicate APP-connected genes specific for MOG_7dpi specific genes after subtraction of ONT_7 genes. APP-responsive genes at day of clinical manifestation of the disease (d1EAE) (D) and in ONT_14 (E). Pointed arrowheads represent activating relationships, dashed lines indicate indirect activation and solid lines direct activation. Red lines point to genes in the network that are involved in the biological processes “neural apoptosis” or “immune response.
Mentions: Comparison of APP-responsive gene set in preclinical EAE (MOG_7dpi) with sequentially regulated genes in clinical manifest EAE (d1EAE) as well as/or in ONT revealed that APP-dependent gene-regulation seems to be a specific phenomenon for the early phase of EAE (Fig 2).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University Medicine Göttingen, Göttingen, Germany.

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.

No MeSH data available.


Related in: MedlinePlus