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알츠하이머 질환 모델 동물에서 p35 유전자 결손이 신경세포 사멸 및 인지 기능 손상에 미치는 영향에 관한 연구
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- Authors
- Advisor
- 서유헌
- Major
- 의학과
- Issue Date
- 2012-02
- Publisher
- 서울대학교 대학원
- Abstract
- The activities of Cdk5 and p35 are thought to be important in the pathogenesis of neurodegenerative diseases, including Alzheimer disease (AD). I studied the effect of p35 deletion in Tg2576 mice, an AD animal model. To obtain the desired mice, I crossed p35+/- and p35+/-/Tg2576 mice. p35-/-/Tg2576 (KO/Tg) mice were smaller, displayed higher mortality rates, produced Aβ and exhibited impaired spatial learning and memory at 6 months of age.
Using immunohistochemical approaches, I observed a reduction in the expression of a number of pre- and post-synaptic markers, including synaptophysin and GluR1. In addition, the intensity of MAP-2-positive dendrites extending from neuronal cell bodies was significantly decreased in KO/Tg mice compared with KO/WT and WT/Tg mice. I also detected increased neuronal cell death in the hippocampus, along with diffuse and sparse morphological changes in the alveus region and a dramatic increase in the number of microglial cells. Microglial infiltration in the hippocampus could result in the secretion of soluble high mobility group box-1 protein (HMGB-1). The secretion of HMGB-1 is increased by Aβ, and secretion of this protein promotes neuronal cell death. Moreover, I established that HMGB-1 induced by Aβ in KO/Tg mice induced ER-mediated cell death.
In summary, during the early phases of AD onset, KO/Tg mice have microglial infiltration in the hippocampus and thus increased secretion of soluble HMGB-1. These conditions promote neuronal death, synaptic destruction and behavioral deficits.
- Language
- kor
- URI
- https://hdl.handle.net/10371/156533
http://dcollection.snu.ac.kr:80/jsp/common/DcLoOrgPer.jsp?sItemId=000000002034
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