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The Role of Neuroinflammation in the...
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Frakes, Ashley E.
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The Role of Neuroinflammation in the Pathogenesis of Amyotrophic Lateral Sclerosis.
紀錄類型:
書目-電子資源 : Monograph/item
正題名/作者:
The Role of Neuroinflammation in the Pathogenesis of Amyotrophic Lateral Sclerosis./
作者:
Frakes, Ashley E.
面頁冊數:
200 p.
附註:
Source: Dissertation Abstracts International, Volume: 77-07(E), Section: B.
Contained By:
Dissertation Abstracts International77-07B(E).
標題:
Neurobiology. -
電子資源:
http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10026207
ISBN:
9781339522906
The Role of Neuroinflammation in the Pathogenesis of Amyotrophic Lateral Sclerosis.
Frakes, Ashley E.
The Role of Neuroinflammation in the Pathogenesis of Amyotrophic Lateral Sclerosis.
- 200 p.
Source: Dissertation Abstracts International, Volume: 77-07(E), Section: B.
Thesis (Ph.D.)--The Ohio State University, 2014.
Amyotrophic lateral sclerosis (ALS), or Lou Gehrigs disease, is a fatal neurodegenerative disease affecting motor neurons resulting in severe muscle atrophy, paralysis, and ultimately respiratory failure and death. Typically, ALS strikes people between 40-70 years old, and it is estimated that 5,600 people are diagnosed with this disease in the United States per year. Only one FDA-approved drug, Riluzole, is available for patients, which extends lifespan by only a few months. For the majority of ALS cases, there is no family history of the disease (termed sporadic ALS), making it difficult to identify genetic factors that contribute or cause disease. The remaining 5 to 10% of ALS is inherited in an autosomal dominant fashion (termed familial ALS). Sporadic and familial ALS cases are clinically indistinguishable. One of the most striking hallmarks that is shared by both familial and sporadic ALS is neuroinflammation, characterized by microglial activation, astrogliosis, and infiltration of peripheral immune cells. It is unknown what role neuroinflammation plays in motor neuron (MN) death in ALS. Therefore, the aim of these studies is to identify upstream regulators of inflammation that are dysregulated with disease and to understand the role of this complex response in MN death in ALS.
ISBN: 9781339522906Subjects--Topical Terms:
588707
Neurobiology.
The Role of Neuroinflammation in the Pathogenesis of Amyotrophic Lateral Sclerosis.
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Amyotrophic lateral sclerosis (ALS), or Lou Gehrigs disease, is a fatal neurodegenerative disease affecting motor neurons resulting in severe muscle atrophy, paralysis, and ultimately respiratory failure and death. Typically, ALS strikes people between 40-70 years old, and it is estimated that 5,600 people are diagnosed with this disease in the United States per year. Only one FDA-approved drug, Riluzole, is available for patients, which extends lifespan by only a few months. For the majority of ALS cases, there is no family history of the disease (termed sporadic ALS), making it difficult to identify genetic factors that contribute or cause disease. The remaining 5 to 10% of ALS is inherited in an autosomal dominant fashion (termed familial ALS). Sporadic and familial ALS cases are clinically indistinguishable. One of the most striking hallmarks that is shared by both familial and sporadic ALS is neuroinflammation, characterized by microglial activation, astrogliosis, and infiltration of peripheral immune cells. It is unknown what role neuroinflammation plays in motor neuron (MN) death in ALS. Therefore, the aim of these studies is to identify upstream regulators of inflammation that are dysregulated with disease and to understand the role of this complex response in MN death in ALS.
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Nuclear Factor-kappa B (NF-kappaB), a master regulator of inflammation, is upregulated in glia of both familial and sporadic ALS patients. Our laboratory recently identified this pathway as the highest-ranked regulator of inflammation by Ingenuity Pathway Analysis of gene expression data from familial and sporadic post-mortem ALS astrocytes. In Chapter 2 of this dissertation, we demonstrate that NF-kappaB signaling is upregulated in SOD1-G93A mice, and increases with disease progression. However, selective NF-kappaB inhibition in ALS astrocytes is not sufficient to rescue MN death in vitro or in vivo. Furthermore, to characterize the spacial and temporal localization of NF-kappaB activity in ALS, we crossed the SOD1-G93A mice to an NF-kappaB-GFP reporter strain. While NF-kappaB activity was detected in astrocytes, we identified microglia as the predominant cell-type activating NF-kappaB with disease progression. To further study the potential role of NF-kappaB in microglial-mediated MN death, we established the first robust and reproducible in vitro co-culture model of adult microglia and motor neurons. Utilizing this novel model, we determined inhibiting NF-kappaB signaling in microglia rescued MN survival to near wild-type levels. Subsequent deletion of NF-kappaB signaling in microglia in vivo dampened pro-inflammatory microglial activation and extended survival in ALS mice by 20 days. Conversely, constitutive activation of NF-kappaB selectively in wild-type microglia induced gliosis and MN death in vitro and in vivo. Taken together, these data provide a mechanism by which microglia induce MN death in ALS, and suggest a novel therapeutic target that can be modulated to slow the progression of ALS and possibly other neurodegenerative diseases by which microglial activation plays a role.
520
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In addition to microglia, other cell types such as motor neurons, astrocytes, and oligodendrocytes are involved in ALS pathogenesis. Therefore, we hypothesized that a successful therapeutic strategy is likely to involve targeting multiple cell types and pathogenic mechanisms. Our laboratory previously demonstrated that a single, post-natal, intravenous injection of AAV9 encoding a shRNA against mutant SOD1 is able to traverse the blood-brain-barrier of ALS mice and reduce SOD1-expression in astrocytes and motor neurons. Reducing mutant SOD1 led to a robust increase in survival of 51.5 days. Therefore, to evaluate the benefit of a combinatorial treatment in ALS, we combined microglial NF-kappaB suppression with SOD1 reduction in astrocytes and motor neurons. Targeting all three cell-types resulted in an additive increase in lifespan, with maximum survival reaching 204 days, 67 days longer than the mean survival of control animals. The data for this study is presented in Chapter 4.
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In summary, we identify a novel mechanism by which microglia, but not astrocytes, induce motor neuron death in ALS. Furthermore, we demonstrate targeting two independent pathogenic mechanisms results in an additive increase in survival in the ALS mouse model. This suggests a combinatorial approach should be investigated as a therapeutic paradigm for the treatment of ALS. Future directions and implications of this work are discussed in Chapter 5.
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http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10026207
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