Title

Role of Presenilin 2 in Corticosterone-Induced Autophagic Cell Death and Aging-Associated Senescence of Adult Hippocampal Neural Stem Cells

Alternative Title

성체 해마 신경줄기세포에서 Presenilin 2 (PSEN2)에 의한 스트레스 유도 자가포식성 세포사 및 노화 관련 세포노화 기전 연구

DGIST Authors

Jihyun Hong ; Seong-Woon Yu ; No Soo Kim

Advisor

유성운

Co-Advisor(s)

No Soo Kim

Issued Date

2026

Awarded Date

2026-02-01

Type

Thesis

Description

Presenilin 2, Stress, Senescence, Autophagy, Adult hippocampal neural stem cells, Alzheimer disease

Table Of Contents

Chapter 1. General Introduction 1
1.1 Alzheimer disease (AD): overview and pathogenic mechanisms 1
1.1.1 Hallmarks and pathophysiology of AD 1
1.1.2 Amyloid hypothesis and neurogenic impairment 3
1.1.3 Current therapeutic approaches and limitations 4
1.2 Risk factors in AD 7
1.2.1 Intrinsic (genetic) factors 9
1.2.2 Extrinsic (environmental) factors (stress and aging) 10
1.3 The role of presenilin 2 (PSEN2) 12
1.3.1 Multiple effects of presenilins (PSENs) 12
1.3.2 Presenilin 2, a genetic determinant in AD 14
1.4 Aim and objectives 16
1.4.1 Overall aim 16
1.4.2 Objectives 17
Chapter 2. General Materials and Techniques 18
2.1 General Materials 18
2.1.1 Reagents and resources 18
2.2 General techniques 23
2.2.1 Psen2 N141I knock-in (KI) mouse 23
2.2.2 Behavioral tests: Open field test, Object recognition test, and Y-maze 23
2.2.3 Cell culture and isolation 24
2.2.4 Quantitative RT-PCR 25
2.2.5 Western blot analysis 26
2.2.6 Immunocytochemistry (ICC) 27
2.2.7 Immunohistochemistry (IHC) 27
2.2.8 Statistical analysis 28
Chapter 3. Presenilin 2 regulates CORT-induced autophagic death of ahNSCs 29
3.1 Introduction 29
3.2 Materials and methods 31
3.2.1 Generation of CRISPR/Cas9-mediated knockout (KO) ahNSCs 31
3.2.2 In silico prediction of glucocorticoid response element (GRE) motifs 31
3.2.3 CORT administration 32
3.3 Results 33
3.3.1 Psen2 is required for CORT-induced cell death in ahNSCs 33
3.3.2 Psen2 deletion prevents CORT-induced autophagy in ahNSCs 36
3.3.3 Psen2 N141I mutation does not potentiate CORT-induced cell death in ahNSCs 41
3.3.4 Psen2 N141I mutation does not aggravate CORT-induced hippocampal cognitive deficits 44
Chapter 4. Psen2 N141I mutation accelerates cellular senescence and impairs stem cell maintenance and self-renewal capacity in ahNSCs 48
4.1 Introduction 48
4.2 Materials and methods 49
4.2.1 Proliferation assay (CCK-8 assay) 49
4.2.2 Telomere length assay 49
4.2.3 Senescence-associated β-galactosidase (SA-β-Gal) activity assay 50
4.2.4 Live cell imaging 50
4.2.5 Terminal deoxynucleotidyl transferase dUTP-nick-end labeling (TUNEL) assay 51
4.3 Results 52
4.3.1 Psen2 N141I mutation accelerates aging-dependent decline in hippocampal memory and adult neurogenesis independent of apoptosis 52
4.3.2 Psen2 N141I mutation selectively increases Lamin B1 nuclear abnormalities preferentially in ahNSCs, but not in other cell types 59
4.3.3 Psen2 N141I mutation progressively impairs proliferation and self-renewal during serial passaging of ahNSCs 62
4.3.4 Psen2 N141I mutation promotes passage-dependent replicative senescence in ahNSCs 66
4.3.5 Psen2 N141I mutation enhances mitochondrial ROS accumulation during serial passaging of ahNSCs 70
4.3.6 Aβ-plaque deposition and neuroinflammation are not associated with accelerated senescence in the hippocampus of Psen2 N141I mutant mice 73
Chapter 5. Discussion 76
5.1 Overview of findings 76
5.2 PSEN2-mediated autophagic regulation under stress 76
5.3 PSEN2 dysfunction and aging-associated cellular senescence 78
5.4 Integrated model and implications 79
5.5 Limitations 80
5.6 Future directions 80
5.7 Conclusion 81
References 82
Abstract in Korean 88

URI

https://scholar.dgist.ac.kr/handle/20.500.11750/59591
http://dgist.dcollection.net/common/orgView/200000944974

DOI

10.22677/THESIS.200000944974

Degree

Doctor

Department

Department of Brain Sciences

Publisher

DGIST

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