2026-09-21T12:00:34Zhttps://repository.ajou.ac.kr/oai/request

oai:repository.ajou.ac.kr:201003/76372024-10-11T02:17:40Zcom_201003_14369com_201003_14368col_201003_14371

Modulation of Alzheimer’s Disease Pathology by Collagen-Induced Rheumatoid Arthritis in APP/PS1 Mice 콜라겐 유도에 의한 관절염이 치매동물의 병리기전에 미치는 영향에 관한 연구 박, 선미 조, 은혜 곽, 병주 대학원 의학과 200624087 박, 선미 Alzheimer’s disease (AD) Rheumatoid arthritis (RA) Inflammation Blood-brain barrier (BBB) Amyloid beta (Aβ) Several evidences suggest that rheumatoid arthritis (RA) may enhance or reduce the progression of Alzheimer’s disease (AD). The present study was performed to directly explore the effects of collagen-induced rheumatoid arthritis (CIA) on cognitive function, amyloid plaque formation, microglial activation, and cerebrovascular pathology in the cortex and hippocampus of the double transgenic APP/PS1 mouse model for AD. Wild-type or APP/PS1 mice that received type II collagen (CII) in complete Freund’s adjuvant (CFA) at presymptomatic stage (2 months) or postsymptomatic stage (8.5 months) of age revealed characteristics of RA, such as joint swelling, synovitis, and cartilage and bone degradation 4 months later. Joint pathology was accompanied by sustained induction of IL-1β and TNF-α in plasma over 4 weeks after administration of CII in CFA. In the presymptomatic stage, prior to the onset of plaque formation, CIA reduced levels of soluble and insoluble amyloid beta (Aβ peptides) and amyloid plaque formation in the cortex and hippocampus of APP/PS1 mice, which correlated with increased blood brain barrier disruption, Iba-1 or Mac-1 positive microglia, and CD45-positive microglia/macrophages. In contrast, CIA reduced survival and vessel density and length with features of cerebrovascular pathology including vascular segments, thinner vessels, and atrophic string vessels. In the postsymptomatic stage, after the onset of amyloid plaque formation, CIA mice improved cognitive function behavior based on the performance in the MWM and the Y-Maze and reduced amyloid plaque pathology. Additionally CIA mice increased cerebrovascular pathology and mortality. The present findings suggest that RA may exert beneficial effects against Aβ burden and harmful effects on cerebrovascular pathology and mortality in AD. However, the chronic systemic inflammation causes cerebrovascular pathology, which likely aggravates pathology and neurological deficit in APP/PS1 and possibly AD patients. ABSTRACT i TABLE OF CONTENTS iii LIST OF FIGURES vi LIST OF TABLES viii LIST OF ABBREVATION ix I.INTRODUCTION 1 A. Overview 1 B. Alzheimer’s disease (AD) and inflammation 3 C. Neuroinflammation 4 D. Systemic inflammation and AD 5 E. Vascular dysfunction 7 F. Aβ degradation enzyme 8 G. Rheumatoid arthritis (RA) 9 H. Specific aims of the study 11 II.MATERIALS AND METHODS 12 A.MATERIALS 12 1. Animals 12 2. Reagents 12 B. METHODS 13 1. Induction of CIA 13 2. Analysis of plasma IL-1β and TNF-α 13 3. Tissue preparation 13 4. Aβ ELISA 14 5. Immunohistochemistry 14 6. Image analysis of amyloid plaque burden, activated microglia/macrophages, and vascular pathology 15 7. Extravasation of Evans blue (EB) and IgG Western blotting 16 8. Aβ degradation enzyme ELISA 16 9. Quantitative real-time PCR 17 10. Morris water maze (MWM) 17 11. Y-Maze 18 12. Statistical analysis 19 III. RESULTS 20 A. Effects of CIA on presymptomatic stage of APP/PS1 mice 20 1. Induction of collagen-induced arthritis (CIA) in APP/PS1 mice 20 2. Effects of CIA on amyloid plaque pathology in APP/PS1 mice 25 3. Enhanced activation of microglia/macrophages in APP/PS1 mice 28 4. Effects of CIA on permeability of the blood-brain barrier (BBB) in APP/PS1 mice 34 5. Effects of CIA on cerebrovascular pathology in APP/PS1 mice 37 6. Effects of CIA on mortality in APP/PS1 40 B. Effects of CIA on postsymptomatic stage of APP/PS1 mice 41 1. CIA improves spatial learning and memory in APP/PS1 mice 41 (1) Morris water maze (MWM) 41 (2) Y-Maze 41 2. CIA reduces amyloid plaque burden 45 3. CIA reduces Aβ peptide levels 47 4. CIA reduces microglial activation 48 5. CIA increases tPA activity and decreases PAI-1 (tPA inhibitor) 51 6. CIA reduces oxidative stress in APP/PS1 mice 54 7. CIA enhances the permeability of the BBB and the pathology of the cerebrovessel 56 8. CIA enhances mortality in APP/PS1 59 IV. DISCUSSSION 64 V. CONCLUSION 72 REFERENCES 73 국문요약 87 Doctor 2012-11-06T01:12:01Z 2012-11-06T01:12:01Z 2012 2012 Thesis Theses http://repository.ajou.ac.kr/handle/201003/7637 http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000012215 000000012215 en