108 188

Cited 0 times in

Modulation of Alzheimer’s Disease Pathology by Collagen-Induced Rheumatoid Arthritis in APP/PS1 Mice

DC Field Value Language
dc.contributor.author박, 선미-
dc.date.accessioned2012-11-06T01:12:01Z-
dc.date.available2012-11-06T01:12:01Z-
dc.date.issued2012-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/7637-
dc.description.abstractSeveral 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.
-
dc.language.isoen-
dc.titleModulation of Alzheimer’s Disease Pathology by Collagen-Induced Rheumatoid Arthritis in APP/PS1 Mice-
dc.title.alternative콜라겐 유도에 의한 관절염이 치매동물의 병리기전에 미치는 영향에 관한 연구-
dc.typeThesis-
dc.identifier.urlhttp://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000012215-
dc.subject.keywordAlzheimer’s disease (AD)-
dc.subject.keywordRheumatoid arthritis (RA)-
dc.subject.keywordInflammation-
dc.subject.keywordBlood-brain barrier (BBB)-
dc.subject.keywordAmyloid beta (Aβ)-
dc.description.tableOfContentsABSTRACT 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
-
dc.description.degreeDoctor-
dc.contributor.affiliatedAuthor박, 선미-
dc.date.awarded2012-
dc.type.localTheses-
dc.citation.date2012-
Appears in Collections:
Theses > School of Medicine / Graduate School of Medicine > Doctor
Files in This Item:
000000012215.pdfDownload

qrcode

해당 아이템을 이메일로 공유하기 원하시면 인증을 거치시기 바랍니다.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse