Title

A human telomerase reverse transcriptase-derived peptide GV1001 rescues neurodegeneration in a mouse model of Alzheimer disease

Alternative Title

인간 텔로머라제 역전사효소 유래 펩타이드 GV1001에 의한 알츠하이머병 마우스모델에서 신경퇴행성 회복과 그 심층기전

DGIST Authors

Younghwan Lee ; Seong-Woon Yu ; Sung Joong Lee

Advisor

유성운

Co-Advisor(s)

Sung Joong Lee

Issued Date

2025

Awarded Date

2025-08-01

Type

Thesis

Description

GV1001, Alzheimer disease, microglia, bradykinin receptor 1, migration, phagocytosis, MTORC2

Table Of Contents

List of Contents
Abstract i
List of Contents ii
List of Figures v
List of Tables vii
List of Abbreviations viii

Chapter 1. Introduction 1
1.1 Alzheimer disease (AD) and drug development 1
1.1.1 AD: History and features 1
1.1.2 Drug development for AD 2
1.1.3 GV1001: promising AD therapeutic 3
1.2 Microglia: The central player in neurodegeneration 7
1.2.1 The developmental origin of microglia and a brief history of microglia study 7
1.2.2 Pathophysiological roles of microglia 9
1.3 Kallikrein-kinin system (KKS) 14
1.3.1 KKS and inflammation 14
1.3.2 KKS in central nervous system (CNS) 17

Chapter 2. General materials and techniques 18
2.1 General materials 18
2.1.1 Reagent and resource 18
2.2 General techniques 22
2.2.1 Animals 22
2.2.2 Cell culture and isolation 22
2.2.3 Quantitative RT-PCR 23
2.2.4 Western blot analysis 23
2.2.5 Immunocytochemistry 24

2.2.6 Immunohistochemistry (IHC) 25
2.2.7 Statistical analysis 25

Chapter 3. GV1001 rescues AD pathogenesis of 5xFAD mice 27
3.1 Introduction 27
3.2 Materials and methods 31
3.2.1 GV1001 administration 31
3.2.2 Behavior test: open field test, object recognition test and Y-maze 31
3.2.3 Golgi-Cox staining 32
3.2.4 Prussian blue staining 32
3.2.5 Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay 32
3.2.6 Proximity ligation assay (PLA) 33
3.2.7 scRNA-seq 33
3.2.8 Preprocessing and quality control 34
3.2.9 Normalization, clustering and differential expression analysis 34
3.2.10 Pseudotime, gene ontology and gene module score analysis 35
3.3 Results 36
3.3.1 GV1001 crosses the blood-brain barrier (BBB) and recovers memory and synaptic degeneration in 5xFAD mice 36
3.3.2 GV1001 reduces Aβ plaque burden and neuroinflammation in 5xFAD mice 40
3.3.3 GV1001 increases phagocytic microglia around the Aβ plaques in 5xFAD mice 43
3.3.4 GV1001 promotes DAM2 transition and increases microglial migration 48
3.4 Discussion 57

Chapter 4. GV1001 promotes microglial migration and phagocytosis in B1R-dependent manner 58
4.1 Introduction 58
4.2 Materials and methods 59
4.2.2 Ligand-based virtual target simulation (LBVS) 59
4.2.3 Peptide-protein docking simulation 59
4.2.4 Biotin-streptavidin pull down assay· 60
4.2.5 Aβ uptake assay 60
4.3 Results 61
4.3.1 Target prediction and verification using LBVS and peptide-protein docking simulation 61
4.3.2 Inhibition of B1R blocks GV1001-induced microglial migration and phagocytosis 67
4.3.3 Inhibition of B1R blocks amyloidolytic effects and memory recovery of GV1001 in 5xFAD mice 71
4.4 Discussion 75

Chapter 5. In-depth analysis of molecular mechanism of GV1001 76
5.1 Introduction 76
5.2 Results 78
5.2.1 MTORC2 mediates GV1001-induced microglia phagocytosis and migration with lamellipodium formation 78
5.2.2 GV1001 increases CLEC7A+ DAM2 in a B1R-dependent manner 85
5.4 Discussion 87

Chapter 6. Discussion 89

References 93
Abstract in Korean 102

URI

https://scholar.dgist.ac.kr/handle/20.500.11750/59755
http://dgist.dcollection.net/common/orgView/200000888358

DOI

10.22677/THESIS.200000888358

Degree

Doctor

Department

Department of Brain Sciences

Publisher

DGIST

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