Exploring neuroinflammatory processes in a mouse model of amyotrophic lateral sclerosis
<p>Amyotrophic lateral sclerosis (ALS) is a devastating degenerative disease, affecting both upper and lower motor neurons in the CNS. Around 10% of ALS cases are classed as familial, and around 20% of these are due to a mutation in the gene superoxide dismutase-1 (SOD1). The SOD1G93A mouse is...
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| Format: | Thesis |
| Language: | English |
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2012
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| _version_ | 1826283835139031040 |
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| author | Evans, M Mr Matthew C Evans |
| author2 | Turner, M |
| author_facet | Turner, M Evans, M Mr Matthew C Evans |
| author_sort | Evans, M |
| collection | OXFORD |
| description | <p>Amyotrophic lateral sclerosis (ALS) is a devastating degenerative disease, affecting both upper and lower motor neurons in the CNS. Around 10% of ALS cases are classed as familial, and around 20% of these are due to a mutation in the gene superoxide dismutase-1 (SOD1). The SOD1G93A mouse is one of the transgenic rodent models of this disease. Both in humans and animal models of ALS, neuroinflammation is an important theme that has attracted much research attention over the past few decades. An area that has attracted much less attention, though, is the neurovascular aspect of pathology. In both these fields, the literature is biased towards the spinal cord, with little information available about SOD1 pathology in other CNS regions. In this context, we sought to investigate pathological components of ALS pathology throughout the CNS, using a multi-disciplinary approach. First, I explore the use of MRI as in in vivo biomarker of brainstem pathology, showing that ALS pathology can be tracked using short sequences, paving the way for MRI as a high-throughput biomarker for clinical trials. Secondly, I use in vivo MRI and immunohistochemistry to investigate vascular and inflammatory components of the pathology. I show that there is very little cellular adhesion molecule expression in the CNS of SOD1G93A mice, despite post-symptomatic expression of cytokines and chemokines, and no disruption to the BBB at any point in the disease. Finally, I investigate whether steroids have therapeutic value in SOD1G93A mice, when delivered specifically into the CNS using targeted liposomes, and show that centrally-targeted methylprednisolone has a significant impact of brainstem pathology, but no effect on spinal pathology in this model. </p> <p>In summary, inflammation is a key aspect of SOD1G93A pathology, although changes in the permeability of the BBB may be more contentious than the previous literature would suggest. Targeting inflammatory processes using more targeted approaches may offer hope for development of therapies for ALS in the future.</p> |
| first_indexed | 2024-03-07T01:04:49Z |
| format | Thesis |
| id | oxford-uuid:8af7e13e-96df-4b87-84aa-4e1bb25ae886 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:04:49Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:8af7e13e-96df-4b87-84aa-4e1bb25ae8862022-03-26T22:35:02ZExploring neuroinflammatory processes in a mouse model of amyotrophic lateral sclerosisThesishttp://purl.org/coar/resource_type/c_db06uuid:8af7e13e-96df-4b87-84aa-4e1bb25ae886NeuroscienceBiology (medical sciences)Medical SciencesMotor neurone degenerative diseasePathologyEnglish2012Evans, MMr Matthew C EvansTurner, MSibson, N<p>Amyotrophic lateral sclerosis (ALS) is a devastating degenerative disease, affecting both upper and lower motor neurons in the CNS. Around 10% of ALS cases are classed as familial, and around 20% of these are due to a mutation in the gene superoxide dismutase-1 (SOD1). The SOD1G93A mouse is one of the transgenic rodent models of this disease. Both in humans and animal models of ALS, neuroinflammation is an important theme that has attracted much research attention over the past few decades. An area that has attracted much less attention, though, is the neurovascular aspect of pathology. In both these fields, the literature is biased towards the spinal cord, with little information available about SOD1 pathology in other CNS regions. In this context, we sought to investigate pathological components of ALS pathology throughout the CNS, using a multi-disciplinary approach. First, I explore the use of MRI as in in vivo biomarker of brainstem pathology, showing that ALS pathology can be tracked using short sequences, paving the way for MRI as a high-throughput biomarker for clinical trials. Secondly, I use in vivo MRI and immunohistochemistry to investigate vascular and inflammatory components of the pathology. I show that there is very little cellular adhesion molecule expression in the CNS of SOD1G93A mice, despite post-symptomatic expression of cytokines and chemokines, and no disruption to the BBB at any point in the disease. Finally, I investigate whether steroids have therapeutic value in SOD1G93A mice, when delivered specifically into the CNS using targeted liposomes, and show that centrally-targeted methylprednisolone has a significant impact of brainstem pathology, but no effect on spinal pathology in this model. </p> <p>In summary, inflammation is a key aspect of SOD1G93A pathology, although changes in the permeability of the BBB may be more contentious than the previous literature would suggest. Targeting inflammatory processes using more targeted approaches may offer hope for development of therapies for ALS in the future.</p> |
| spellingShingle | Neuroscience Biology (medical sciences) Medical Sciences Motor neurone degenerative disease Pathology Evans, M Mr Matthew C Evans Exploring neuroinflammatory processes in a mouse model of amyotrophic lateral sclerosis |
| title | Exploring neuroinflammatory processes in a mouse model of amyotrophic lateral sclerosis |
| title_full | Exploring neuroinflammatory processes in a mouse model of amyotrophic lateral sclerosis |
| title_fullStr | Exploring neuroinflammatory processes in a mouse model of amyotrophic lateral sclerosis |
| title_full_unstemmed | Exploring neuroinflammatory processes in a mouse model of amyotrophic lateral sclerosis |
| title_short | Exploring neuroinflammatory processes in a mouse model of amyotrophic lateral sclerosis |
| title_sort | exploring neuroinflammatory processes in a mouse model of amyotrophic lateral sclerosis |
| topic | Neuroscience Biology (medical sciences) Medical Sciences Motor neurone degenerative disease Pathology |
| work_keys_str_mv | AT evansm exploringneuroinflammatoryprocessesinamousemodelofamyotrophiclateralsclerosis AT mrmatthewcevans exploringneuroinflammatoryprocessesinamousemodelofamyotrophiclateralsclerosis |