Title

Elucidating the pathological contribution of APOE4 to Alzheimer’s disease using hiPSC-derived astrocytes and neurons

Alternative Title

인간 유도만능줄기세포 유래 성상교세포와 신경세포를 이용한 APOE4 유전형이 알츠하이머의 발병에 미치는 영향 규명

DGIST Authors

Hyein Lee ; Jinsoo Seo ; Sung Bae Lee

Advisor

서진수

Co-Advisor(s)

Sung Bae Lee

Issued Date

2024

Awarded Date

2024-02-01

Citation

Hyein Lee. (2024). Elucidating the pathological contribution of APOE4 to Alzheimer’s disease using hiPSC-derived astrocytes and neurons. doi: 10.22677/THESIS.200000730288

Type

Thesis

Description

Alzheimer's disease;APOE4;lysosomal cholesterol;APOE Christchurch

Table Of Contents

I. Chapter Ⅰ 1
1.1 Abstract 2
1.2 Introduction 3
1.3 Materials and methods 4
1.4 Results 11
1.4.1 Generation of isogenic APOE hiPSC-derived astrocytes 11
1.4.2 Altered glucose metabolism toward enhanced aerobic glycolysis in ApoE4 astrocytes 11
1.4.3 Impaired mitochondrial respiration with increased ROS in ApoE4 astrocytes 15
1.4.4 Impacts of altered glycolytic activity by ApoE4 in astrocytes 19
1.4.5. Impaired autophagy flux in ApoE4 astrocytes 19
1.4.6 ApoE4-dependent lysosomal cholesterol accumulation impairs autophagic activity and mitochondrial homeostasis in human astrocytes 22
1.4.7 Abnormal mitochondrial respiration, but not glycolytic activity, was restored by lysosomal cholesterol depletion in ApoE4 astrocytes 26
1.4.8 Proteomic analysis confirmed the effects of cholesterol accumulation on mitophagy activity in ApoE4 astrocytes 30
1.5 Discussion 36
1.6 References 38
1.7 Graphical summary 43
II. Chapter Ⅱ 44
2.1 Abstract 45
2.2 Introduction 46
2.3 Materials and methods 48
2.4 Results 52
2.4.1 Generation of APOE4ch iPSCs by CRISPR-Cas9 genome editing system and its differentiation into astrocytes and neurons 52
2.4.2 APOE4-induced transcriptomic alterations are significantly attenuated by the Ch variant in astrocytes 52
2.4.3 Ch variant increases Aβ and tau clearance in astrocytes 55
2.4.4 ApoE4ch increases the LRP1 expression and lowers binding affinity with LRP1 55
2.4.5 APOEch variant reinstates cellular cholesterol homeostasis and reduces mitochondrial ROS in astrocytes 57
2.4.6 Ch variant mitigates APOE4-induced transcriptomic alterations in neurons 60
2.4.7 Christchurch variant mitigates endosomal disruption induced by APOE4 and enhances autophagic degradation of tau proteins 62
2.5 Discussion 66
2.6 References 68
2.7 Graphical summary 73
III. Discussion 74
IV. References 76
V. Korean abstract 77

URI

http://hdl.handle.net/20.500.11750/48001
http://dgist.dcollection.net/common/orgView/200000730288

DOI

10.22677/THESIS.200000730288

Degree

Doctor

Department

Department of Brain Sciences

Publisher

DGIST

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