P301L 형질전환 마우스에서 FAF1과 Neurofibrillary tangles에 의한 basal forebrain의 콜린성 신경세포 사멸
Fas-associated factor 1 is involved in neurofibrillary tangle-mediated cell death of basal forebrain cholinergic neurons in P301L transgenic mice
- 주제(키워드) P301L transgenic mice , septal region , tau phosphorylation , Alzheimer's disease
- 발행기관 아주대학교
- 지도교수 이영돈
- 발행년도 2016
- 학위수여년월 2016. 2
- 학위명 박사
- 학과 및 전공 일반대학원 의생명과학과
- 실제URI http://www.dcollection.net/handler/ajou/000000021554
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Dysfunction of the cholinergic system of the basal forebrain complex is one of the major contributors to cognitive impairment in Alzheimer’s disease (AD). In AD, degeneration of cholinergic fibers that project to the cerebral cortex and hippocampus may be attributed to the development of neurofibrillary tangles (NFT). Here, we evaluated the relationship between neurofibrillary changes and degeneration of septal cholinergic neurons in P301L tau transgenic mice. The number of cholinergic neurons in medial septum and vertical limb of the diagonal band of Broca (MS/VDB) in the basal forebrain were significantly reduced in P301L mice, compared with age-matched wild-type mice. The phospho-tau levels and NFT formation in these P301L mice were higher than wild-type mice. However, it is still unknown how the development of NFT is caused in AD and AD-like pathology. Our results show that Fas-associated factor 1 (FAF1) expression as well as caspase3 activation raised in AT8-positive MS/VDB cholinergic neurons. Furthermore, AT8-positive PHF formation was increased in proportion to FAF1 expression and caspase3 activation in MS/VDB cholinergic neurons. Based on the collective findings, we suggest that increased FAF1 expression triggers caspase-3 cleavage and activation, leading to hyperphosphorylated tau aggregation and subsequent NFT formation, in turn, initiating apoptosis in MS/VDB cholinergic neurons.
more목차
PART I 1
Ⅰ. INTRODUCTION 2
A. Basal forebrain of mammals 2
B. Neuron types in the basal forebrain 2
C. Alzheimer’s disease 3
D. Normal functions of tau protein 4
E. Structure and Posttranslational Modifications of the Tau Protein 5
F. Distribution of tau phosphorylation sites and NFT formation in AD brains 7
G. Monoclonal antibody AT8 recognizes tau phosphorylation 11
H. Cholinergic dysfunction in the basal forebrain in AD cases 12
I. FTDP-17 13
J. Cholinergic dysfunction in P301L transgenic mice 14
Ⅱ. MATERIALS AND METHODS 16
1. Animals 16
2. Antibodies 16
3. Immunohistochemistry 16
4. Thioflavin-S staining 17
5. Sarkosyl fraction of Tau protein and immunoblotting 17
6. Stereological analysis 18
7. Statistical analysis 19
Ⅲ. RESULTS 20
Ⅳ. DISCUSSION 28
Ⅴ. CONCLUSION 30
PART II 31
ABSTRACT 32
Ⅰ. INTRODUCTION 34
A. Reelin expression in GABAergic neurons 34
B. Reelin structure 36
C. Reelin fragments 38
D. Reelin receptors and reelin signaling 39
E. The involvement of Reelin signaling in neuropsychiatric disorders 41
F. Astrogliosis 41
Ⅱ. MATERIALS AND METHODS 44
1. Animals 44
2. Brain section preparation and Immunohistochemistry 44
3. Stereological analysis 45
4. Western blot analysis 45
5. Statistical analysis 46
Ⅲ. RESULTS 47
Ⅳ. DISCUSSION 64
Ⅴ. CONCLUSION 66
CONCLUSION OF PART I, II 67
PART III 69
ABSTRACT 70
Ⅰ. INTRODUCTION 72
A. Mammalian neocortex 73
B. Reelin function in the developing cortex 73
C. Preplate and preplate splitting 75
Ⅱ. MATERIALS AND METHODS 77
1. Animals 77
2. Production of recombinant Reelin 77
3. Culture of neurospheres 78
4. Immunofluorescence 79
Ⅲ. RESULTS 81
Ⅳ. DISCUSSION 99
Ⅴ. CONCLUSION 103
REFERENCES 104
국문요약 116
