초록 ▼

$\circ$ Okadaic acid로 유도한 신경퇴행모델"을 이용하여 GSK-3${\beta}$/protein phosphatase 2A 불균형 및 amyloid precursor protein (APP)의 과발현 기전을 이해하고, 신경세포보호효과가 확인된 GSK-3${\beta}$억제제의 작용기전을 규명하고, Cathepsin D, B, L, S inhibitor인 pepstatin A, CA-074-Me, z-FF-FMK, z-FL-COCHO등의 Autophago -

$\circ$ Okadaic acid로 유도한 신경퇴행모델"을 이용하여 GSK-3${\beta}$/protein phosphatase 2A 불균형 및 amyloid precursor protein (APP)의 과발현 기전을 이해하고, 신경세포보호효과가 확인된 GSK-3${\beta}$억제제의 작용기전을 규명하고, Cathepsin D, B, L, S inhibitor인 pepstatin A, CA-074-Me, z-FF-FMK, z-FL-COCHO등의 Autophago - Lysosome효소억제제와 calpain억제제, caspase억제제, Lactacystine, MG132등 proteosome inhibitor를 농도별로 처리한 후 LDH & MTT assay를 통해 세포보호효과를 분석하였음.
$\circ$ calpain inhibitor와 GSK3b억제제가 APP축적과 APP processing에 미치는 영향 및 기전을 규명하고, 나아가 이 모델을 알쯔하이머 병의 예방 및 치료제 개발을 위한 약물 검색 시스템으로 활용하여 다양한 약물을 구입하여 뛰어난 효능을 가진 선도물질을 발굴하였음.
$\circ$ Triple transgenic mouse(APP, PS1, tau)에서 이들 약물의 효과를 검증하고 당뇨쥐에서 tau 단백질 인산화와 아밀로이드 전구단백질의 대사경로를 상세히 조사하여 알츠하이머와의 연관성을 조사 함.

Abstract ▼

Glycogen synthase kinase-3beta (GSK3beta) is recognized as one of major kinases to phosphorylate tau in Alzheimer's disease (AD), thus lots of AD drug discoveries target GSK3beta. However, the inactive form of GSK3beta which is phosphorylated at serine-9 is increased in AD brains. This is also incon

Glycogen synthase kinase-3beta (GSK3beta) is recognized as one of major kinases to phosphorylate tau in Alzheimer's disease (AD), thus lots of AD drug discoveries target GSK3beta. However, the inactive form of GSK3beta which is phosphorylated at serine-9 is increased in AD brains. This is also inconsistent with phosphorylation status of other GSK3beta substrates, such as beta-catenin and collapsin response mediator protein-2 (CRMP2) since their phosphorylation is all increased in AD brains. Thus, we addressed this paradoxical condition of AD in rat neurons treated with okadaic acid (OA) which inhibits protein phosphatase - 2A (PP2A) and induces tau hyperphosphorylation and cell death. Interestingly, OA also induces phosphorylation of GSK3beta at serine-9 and other substrates including tau, beta-catenin and CRMP2 like in AD brains. In this context, we observed that GSK3beta inhibitors such as lithium chloride and 6-bromoindirubin-3'-monoxime (6-BIO) reversed those phosphorylation events and protected neurons. These data suggest that GSK3beta may still have its kinase activity despite increase of its phosphorylation at serine-9 in AD brains at least in PP2A-compromised conditions and that GSK3beta inhibitors could be a valuable drug candidate in AD Increasing evidence supports an association between Alzheimer's disease (AD) and diabetes. Rosiglitazone, a peroxisome proliferator-activated receptor-$\gamma$ (PPAR$\gamma$) agonist, which is an anti-diabetic agent against type 2 diabetes, is currently in Phase III clinical trials in AD patients because rosiglitazone reduces ${\beta}$-amyloid (A${\beta}$) pathology and inflammation. However, few studies have investigated whether rosiglitazone affects tau phosphorylation, another critical pathological feature of AD. Thus, we investigated it using OLETF type 2 diabetic rats and streptozotocin-injected type 1 diabetic mice. Interestingly, rosiglitazone reduced tau phosphorylation only in the hippocampus of OLETF type 2 diabetes rats, and not in that of STZ-injected type 1 diabetes mice. Levels of phosphorylated JNK were reduced in thehippocampus of rosiglitazone-treated OLETF rats, correlating with a reduction in tau phosphorylation. Phosphorylation of eukaryotic initiation factor-2${\alpha}$ (eIF2${\alpha}$), double-stranded RNA-dependent protein kinase (PKR) and PKR-like endoplasmic reticulum kinase (PERK) were reduced in the hippocampus of rosiglitazone-treated OLETF rats, suggesting a reduction in stress. Hence, rosiglitazone could be used in reducing tau phosphorylation and stress response to ameliorate memory disturbances in type 2 diabetes related Alzheimer's disease.

목차 Contents

• I. 총괄현황 ... 1
• 1. 표지 ... 2
• 2. 제출문 ... 4
• 3. 보고서 요약서 ... 5
• 4. 요약문 (한글) ... 6
• 5. 요약문 (영문) ... 8
• 6. 연구 성과 실적 및 향후 계획 ... 9
• 7. 참여연구원 현황표 ... 13
• II. 총괄연구과제 연구결과 ... 14
• 1. 연구개발과제의 배경 및 필요성 ... 15
• 2. 국내외 기술개발 현황 ... 15
• 3. 연구개발과제의 추진체계 ... 19
• 4. 연구개발수행 내용 및 결과 ... 20
• 5. 목표달성도 및 관련분야 기여도 ... 35
• 6. 향후 연구성과 추진 계획 ... 36
• 7. 연구개발결과의 파급효과 ... 36
• 8. 연구개발결과의 활용계획 ... 37
• 9. 연구개발과정에서 수집한 해외과학기술정보 ... 37
• 10. 참고문헌 ... 37
• IV. 첨부서류 ... 38
• 1. 자체평가의견서 ... 40
• 2. 실적 증빙자료 ... 44
• 3. 기타 첨부서류 ... 45