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Graduate School of Ajou University
Department of Neuroscience and Technology Course
3. Theses(Master)
베타-시크리테아제 발현 조절 기전에 관한 연구
- Alternative Title
- Hyun Jin Cho
- Author(s)
- 조현진
- Alternative Author(s)
- Hyun Jin Cho
- Advisor
- 허균
- Department
- 일반대학원 신경과학기술과정
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2007-08
- Language
- eng
- Keyword
- promoter; JAK/STAT; calcium homeostasis; calcineurin/NFAT; RAGE
- Alternative Abstract
- Alzheimer’s disease (AD) is the most common form of senile dementia characterized by senile plaques, neurofibrillary tangles and neuronal loss. Aβ peptide, a major component of senile plaques, is involved in the pathological events that result in the clinical symptoms of AD. Prominent inflammatory response and disruption of intracellular calcium homeostasis are also observed in AD pathogenesis. BACE1 (β-site APP cleaving enzyme) is an essential enzyme for Aβ generation. It has been reported that the levels of BACE1 expression and enzymatic activity are elevated in sporadic AD cases compared to age-matched normal brains. In this study, we hypothesized that BACE1 expression is regulated at the transcriptional level by dissecting BACE1 promoter. We found IFN-γ, pro-inflammatory cytokine, activated JAK2 and ERK1/2 and then phosphorylated STAT1 binds to the putative STAT1 binding sequences in BACE1 promoter region, resulting in modulating BACE1 gene expression in astrocytes. In late-onset of AD, aging is the most important risk factor and contributes to increasing in abnormal accumulation of Aβ and the disruption of calcium homeostasis. We examined the role of NFAT1, which is a transcription factor regulated in neurons. Treatment of calcium ionophore or Aβ, which is known to elevate intracellular calcium level, elevated BACE1 expression via calcineurin/NFAT1 signaling pathway. Since expression of RAGE (receptor for advanced glycation endproducts), a multiligand receptor for AGEs and Aβ, is elevated in the brains of aged individuals as well as AD patients, the role of RAGE in BACE1 expression was examined. We found that NFAT1 activation and BACE1 expression were enhanced in RAGE overexpressing neurons. Taken together, BACE1 expression was regulated at the transcription level in the pathological environment of AD. It suggests possible targets to develop Aβ-lowering drugs for AD pathogenesis.
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- Graduate School of Ajou University > Department of Neuroscience and Technology Course > 3. Theses(Master)
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