콜라겐 유도에 의한 관절염이 치매동물의 병리기전에 미치는 영향에 관한 연구
Modulation of Alzheimer’s Disease Pathology by Collagen-Induced Rheumatoid Arthritis in APP/PS1 Mice
- 주제(키워드) Alzheimer’s disease (AD) , Rheumatoid arthritis (RA) , Inflammation , Blood-brain barrier (BBB) , Amyloid beta (Aβ)
- 발행기관 아주대학교
- 지도교수 조은혜 곽병주
- 발행년도 2012
- 학위수여년월 2012. 2
- 학위명 박사
- 학과 및 전공 일반대학원 의학과
- 실제URI http://www.dcollection.net/handler/ajou/000000012215
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
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.
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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
