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Graduate School of Ajou University
Department of Neuroscience and Technology Course
3. Theses(Master)
전신성허혈과 알츠하이머 병의 동물 모델에서 혈뇌장벽손상의 병리적인 역할
- Alternative Title
- Pathological roles of blood-brain barrier damage in animal models of stroke and alzheimer's disease
- Author(s)
- Won, Sun Mi
- Alternative Author(s)
- Sun Mi Won
- Advisor
- 곽병주
- Department
- 일반대학원 신경과학기술과정
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2010-08
- Language
- eng
- Keyword
- Free radical; Transient forebrain ischemia; alzheimer; amyloid beta; blood-brain barrier; iron
- Alternative Abstract
- Recent data from humans and animals models suggest that pathological blood-brain barrier (BBB) opening contributes to nerve cell damage and dysfunction. We examined the possibility and underlying mechanims that transient forebrain ischemia (TFI) would render the BBB permeable to blood cells possibly through dysfunction and degeneration of endothelial cells. Extravasation of blood cells into the hippocampal parenchyma was manifest by increased levels of Evans blue and IgG that were detectable at 8 h and peaked at 48 h after TFI. TdT-mediated dUDP nick end labeling (TUNEL) revealed marked degeneration of endothelial cells primarily in the CA1 and 2 area within 48 h after TFI. Mitochondrial free radicals were produced in the endothelial cells as well as the hippocampal neurons before cell death occurred. Iron was overloaded in the microvessel endothelium of the CA1 and 2 area as early as 30 min, was higher than the control until 4 h after reperfusion. Administration of deferoxamine (DFO), a selective iron chelator, or Neu2000, a potent antioxidant, blocked free radical production, degeneration of the endothelial cells, and extravasation of the blood cells into the brain. The present study suggests that iron overload and iron-mediated free radical production cause degeneration of the endothelial cells, opening of the BBB, and possibly degeneration of the CA1 pyramidal neurons after TFI. Evidence has accumulated suggesting that BBB opening and iron deposit are associated with the pathology of Alzheimer’s disease (AD). We examined role of amyloid beta (Ab) peptides underlying initial BBB opening and iron deposit in APP/PS1 (which coexpress mutated human presenilin 1 and amyloid-β precursor protein). BBB opening was barely detectable in APP/PS1 at 3 months of age but significantly elevated in 5-month-old APP/PS1 mice as shown by infiltration of IgG in the cortex and hippocampus. Double staining with Evans blue and a collagen type IV antibody revealed basal lamina disruption and blood extravasation primarily in the cortex. BBB opening was accompanied by reduced levels of tight junction proteins such as occludin and adherence junction protein β-catenin. Soluble Ab40 was detected approximately to 0.35 pg/g at 2 - 5 months of age. In contrast, soluble Ab42 was slightly detected at 3 months of age but both soluble and insoluble forms of Ab42 were increased up to 0.04 and 0.025 pg/g at 5 months of age, respectively. Intracortical administration of soluble Ab42, but not Ab40, caused BBB opening around the injection site, suggesting that soluble Ab42 mediates initial BBB opening in APP/PS1 mice. Iron deposit was observed exclusively in plaques and blood vessels in 5-month-old APP/PS1 mice and following intrahippocampal administration of Ab42. Administration of deferoxamine, a selective iron chelator, for 2 months reduced amyloid plaque burdens as well as iron deposit. Furthermore, amyloid plaque burdens in APP/PS1 mice were locally increased at 15 d following intracortical administration of FeCl2. The present findings suggest that soluble Ab42 enhances amyloid plaque burdens by inducing BBB opening and iron deposit at early stage of AD pathology.
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- Graduate School of Ajou University > Department of Neuroscience and Technology Course > 3. Theses(Master)
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