Dissertation
Characterization of human astrocyte senescence: potential role in aging brain and neurodegenerative disease
Doctor of Philosophy (Ph.D.), Drexel University
May 2014
DOI:
https://doi.org/10.17918/00000633
Abstract
Aging is a major risk factor for cognitive decline and neurodegenerative disease. A key feature of the basic biology of aging is cellular senescence. Cellular senescence is classically defined as an essentially irreversible proliferative growth arrest that is telomere-based, but it can also be induced prematurely by stressors. Senescent cells undergo widespread changes in gene expression, demonstrate an altered, pro-inflammatory secretion pattern, accumulate in tissues during aging and at sites of age-related pathologies in the periphery and it is thought that senescent cells contribute to an age-related decline in tissue function and tumor formation. However, little is known about the potential for central nervous system (CNS)-derived cell types to undergo senescence or their relevance to aging-related cognitive decline and neurodegenerative disease. Given that astrocytes are a highly abundant population of glial cells that perform myriad of complex functions in the CNS in order to maintain homeostasis, the loss of astrocyte function or the gain of neuroinflammatory function as a result of senescence could have profound implications for aging brain and neurodegenerative disorders including AD. We found that human astrocytes exhibit classic biomarkers of the senescent phenotype in vitro in response to exhaustive replication, oxidative stress, and amyloid-beta. To better understand senescence-associated changes in astrocytes at the molecular level, we investigated global changes in the astrocyte transcriptome using a whole transcriptome sequencing method (RNA-seq) following the induction of oxidative stress-induced senescence. Senescent astrocytes downregulate the expression of brain-enriched genes involved in neuronal differentiation and development suggesting a loss of differentiated function in these cells. In addition, senescent astrocytes acquire an inflammatory phenotype indicative of the senescence-associated secretory phenotype (SASP), which seems to be regulated by p38MAPK. In order to begin to establish the physiologic relevance of astrocyte senescence to aging brain and AD, we examined post-mortem frontal cortex for biomarkers of senescence and for glial fibrillary acidic protein (GFAP) to identify astrocytes and found that during aging and AD there is a significant increase in population of senescent astrocytes. Overall, these studies suggest that senescent astrocytes are a component of the age-related neurodegeneration.
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Details
- Title
- Characterization of human astrocyte senescence
- Creators
- Elizabeth Patricia Crowe
- Contributors
- Claudio A. Torres (Advisor)Christian Sell (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 230 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991014970227904721