뇌 기능과 질환에서의 별세포 가소성 기전 연구 : MCT1 의존 반응성 별세포와 PAR1 매개 활성 별세포의 역할

박용민 과학기술연합대학원대학교 기초과학연구원(IBS) 2025 국내박사

별세포는 중추신경계(CNS)의 중요한 구성 요소로, 뉴런에 대사적, 구조적 지지를 제공하면서도 다양한 자극에 민감하게 반응한다. 이러한 반응성 덕분에 별세포는 형태와 기능에서 큰 변화를 겪게 되며, 이를 별세포 가소성이라고 한다. 별세포 가소성은 뇌의 항상성 유지, 시냅스 활동 조절, 손상이나 질병에 대한 반응에 필수적인 역할을 한다. 별세포 가소성을 이해하는 것은 뇌가 어떻게 변화에 적응하고, 별세포 기능이 신경 질환에 어떻게 기여하는지를 밝힘으로써, 별세포가 치료적 개입의 유망한 대상임을 시사한다. 본 논문에서는 별세포 가소성이 뇌 기능과 질병에 어떤 영향을 미치는지 탐구하며, MCT1 의존적인 반응성 별세포와 PAR1 매개 활성 별세포라는 두 가지 유형에 집중한다. 첫 번째 장에서는 반응성 별세포에서 MCT1을 통한 아세테이트 섭취와 이의 신경염증에 미치는 영향을 알츠하이머병(AD)과 교모세포종(GBM)을 중심으로 탐구한다. 반응성 별세포는 MCT1 발현이 증가하면서 아세테이트 섭취가 늘어나고, 이는 대사적 변화를 일으켜 푸트레신 분해 경로를 통한 GABA 합성을 증가시킨다. 이러한 아세테이트 과대사는 뉴런에서 억제성 신호를 유발하고, GLUT3의 발현 저하로 인해 포도당 섭취가 줄어들어 뉴런 기능에 장애를 초래한다. MCT1을 유전적으로 억제함으로써 본 연구는 뉴런 기능 회복 가능성을 보여주며, MCT1이 신경염증 질환의 치료적 타겟으로 유망하다는 것을 제시한다. 두 번째 장에서는 별세포에서 프로테아제 활성화 수용체 1 (PAR1)의 역할과 해마 의존적 기억 형성에 대한 관여를 조사한다. 뇌에서 유래한 트롬빈에 의해 활성화된 별세포의 PAR1은 별세포의 활동을 조절하여 시냅스 가소성과 인지 과정에 중요한 역할을 한다. PAR1 floxed 생쥐 모델을 사용한 연구 결과, 별세포 PAR1의 활성화는 해마의 장기 강화(LTP)와 공간 기억에 필수적임이 밝혀졌다. 풍부한 환경에서의 실험을 통해 PAR1 활성화가 별세포로부터 뇌 유래 신경영양인자(BDNF)와 같은 성장 인자의 전사를 촉진하여 시냅스 가소성과 인지 기능에 중요한 역할을 한다는 것을 확인했다. 이러한 결과는 PAR1이 별세포와 뉴런 간 상호작용의 주요 조절자임을 강조하며, 기억 형성과 시냅스 가소성을 증진시키기 위한 치료적 타겟으로서의 가능성을 보여준다. 이러한 연구 결과는 반응성 별세포와 활성 별세포가 뇌 기능과 병리 조절에 각각 독특하면서도 상호 보완적인 역할을 수행함을 보여준다. MCT1 매개 대사 변화로 활성화된 반응성 별세포는 신경염증 병리학에 기여하는 반면, PAR1 활성화에 의해 조절되는 활성 별세포는 시냅스 가소성과 기억 형성을 돕는다. 본 논문은 별세포 가소성의 분자적 메커니즘에 대한 통찰을 제공하며, 신경염증 질환과 인지 장애 치료를 위한 잠재적 치료 전략을 제시한다. 주요단어(Key words) : 별세포, 별세포 가소성, 반응성 별세포화, MCT1, 아세트산, 활성 별세포, PAR1, 시냅스 가소성, 뇌유래신경영양인자 Astrocytes are essential components of the central nervous system (CNS), providing metabolic and structural support to neurons while actively responding to various stimuli. This responsiveness allows astrocytes to undergo significant morphological and functional changes, known as astrocytic plasticity, which is crucial for maintaining brain homeostasis, modulating synaptic activity, and responding to injury or disease. Understanding astrocytic plasticity is vital as it reveals how the brain adapts to changes and how dysregulated astrocyte function contributes to neurological diseases, making it a promising target for therapeutic interventions. This dissertation explores the roles of astrocytic plasticity in brain function and disease, focusing on two distinct types of astrocytes: MCT1- dependent reactive astrocytes and PAR1-mediated active astrocytes. In the first chapter of my study, I delve into MCT1-mediated acetate uptake in reactive astrocytes and its impact on neuroinflammation, particularly in Alzheimer's disease (AD) and glioblastoma (GBM). Reactive astrocytes exhibit increased expression of MCT1, which enhances acetate uptake and drives metabolic changes, ultimately leading to increased GABA synthesis through the putrescine degradation pathway. This acetate hypermetabolism contributes to aberrant inhibitory signaling in neurons and reduced glucose uptake due to GLUT3 downregulation, leading to neuronal dysfunction. By targeting MCT1 through genetic silencing, this study demonstrates the potential to restore neuronal function, positioning MCT1 as a promising therapeutic target for neuroinflammatory diseases. In Chapter 2, I investigate the role of protease-activated receptor 1 (PAR1) in astrocytes and its involvement in hippocampus-dependent memory formation. Activation of astrocytic PAR1 by brain-derived thrombin modulates astrocytic activity, which is crucial for synaptic plasticity and cognitive processes. Using a PAR1 floxed mouse model, the study demonstrates that astrocytic PAR1 is essential for hippocampal long-term potentiation (LTP) and spatial memory. Enriched environment experiments further reveal that PAR1 activation enhances the transcription of growth factors like brain-derived neurotrophic factor (BDNF), which is key for synaptic plasticity and cognitive performance. These findings underscore PAR1's role in astrocyte-neuron communication and highlight its potential as a therapeutic target to enhance memory and synaptic plasticity. Together, these findings highlight the distinct yet complementary roles of reactive and active astrocytes in regulating brain function and pathology. Reactive astrocytes, driven by MCT1-mediated metabolic changes, contribute to neuroinflammatory pathologies, while active astrocytes, mediated by PAR1 activation, support synaptic plasticity and memory formation. This dissertation provides insights into the molecular mechanisms underlying astrocytic plasticity and suggests potential therapeutic strategies for treating neuroinflammatory diseases and cognitive impairments. Key words : Astrocytes, Astrocytic plasticity, Reactive astrogliosis, MCT1, Acetate, Active astrocytes, PAR1, Synaptic plasticity, Memory formation, BDNF

Studies on astrocytic metabolic plasticity in neuroinflammation and cognitive impairment

Kim, Chae Yeon 연세대학교 일반대학원 2025 국내석사

Neurodegenerative disorders, including Alzheimer’s disease (AD), are characterized not only by the overaccumulation of amyloid-beta (Aβ), but also by chronic neuroinflammation and neuronal loss. Among these pathological features, astrocytic changes represent one of the earliest events observed during AD progression [1]. This suggests that astrocytes may play a pivotal role in disease initiation and progression, rather than merely reacting to damage. Recent findings indicate that astrocytes undergo more rapid and extensive metabolic reprogramming than previously appreciated [2-4]. Contrary to the traditional view of astrocytes as passive supporters of neuronal homeostasis, these glial cells actively reshape their metabolic programs under disease conditions. In this study, I sought to investigate the metabolic dynamics of astrocytes in the context of neuroinflammation, aiming to better understand their contribution to the pathogenesis of AD. In part 1 of my study, I aimed to investigate how astrocytic autophagy responds under neuroinflammatory conditions in vivo. In the brain, toxic protein aggregates are taken up by glial cells, including astrocytes and microglia. This process fundamentally involves autophagy, which serves as a core mechanism for maintaining cellular homeostasis [13]. To monitor the dynamic changes in astrocytic autophagy, I utilized a genetically encoded autophagy sensor specifically designed for in vivo application [23]. Unlike conventional sensors that rely on LC3 overexpression, my approach allows visualization of endogenous autophagic activity, providing a reliable tool for monitoring the dynamic and context dependent nature of astrocyte autophagy. In part 2, I aimed to investigate the contribution of impaired mitochondrial glutamine regulation in astrocytes. Mitochondrial dysfunction is a known driver of oxidative stress and cognitive impairment [part2 1-3], yet the molecular mechanisms remain poorly defined. I focused on the mitochondrial glutamine transporter SLC1A5_var, hypothesizing that its dysfunction is associated with mitochondrial homeostasis and inflammatory responses. Through targeted manipulation of SLC1A5_var, I examined its impact on astrocyte reactivity and behavior. In Parts 1 and 2 of this study, I demonstrated that morphological and autophagic alterations in astrocytes occur via the mitochondrial glutamine transporter variant vii SLC1A5_var and lipopolysaccharide (LPS). These findings will serve as experimental evidence for future research on astrocytic metabolic plasticity in neuroinflammation and cognitive impairment.

Inhibition of ASMase Induces Pyroptotic-lysis of Reactive Astrocytes

정예은 과학기술연합대학원대학교 한국과학기술연구원(KIST) 2025 국내석사

Reactive astrocytes are known to persist in neuroinflammatory environments, contributing to disease progression. In this study explored the impact of LPS on pyroptosis-related markers and gene expression in primary astrocytes and the C8-D1A cell line. LPS stimulation resulted in the upregulation of pyroptosis-associated proteins and genes related to reactive astrocytes, leading to significant morphological alterations in both models. Furthermore, peripheral administration of LPS induced astrocyte activation and pyroptosis in the hippocampus, suggesting a link between peripheral immune stimuli and central nervous system (CNS) inflammation. Additionally, we studied the role of an acid sphingomyelinase (ASMase), in this context. Inhibition of ASMase enhanced pyroptosis by disrupting the repair of GSDMD pores, effectively inducing the death of reactive astrocytes. This outcome correlated with a decrease in glial fibrillary acidic protein (GFAP) expression in the mouse brain, suggesting a potential mechanism to mitigate reactive astrocyte-mediated neuroinflammation. These findings provide a deeper understanding of the mechanisms underlying LPS-induced pyroptosis and the regulation of reactive astrocytes in the CNS. Keywords: astrocytes, reactive astrocytes, pyroptosis, acid sphingomyelinase 반응성 성상세포는 신경염증 환경에서 사멸하지 않고, 질병을 악화시킨다고 알려져 있다. 본 연구에서는 쥐 뇌 조직 유래 성상세포와 C8-D1A 쥐 성상세포 세포주에서 파이롭토시스 관련 유전자 발현 및 세포사멸 유도에 미치는 영향을 조사하였다. LPS 자극은 파이롭토시스와 관련된 마커 및 반응성 성상세포와 관련된 유전자의 발현을 증가시키며, 유의미한 형태학적 변화를 유도하였다. 말초에 LPS를 투여한 결과, 해마에서 성상세포의 활성화와 파이롭토시스가 유도되어 말초 면역 자극과 중추 신경계 염증 간의 연관성을 시사하였다. 더불어 산성 스핑고미엘린 분해효소 저해를 통해 게스다민 구멍 복원을 저해하여 반응성 성상세포의 사멸을 유도함을 확인하였다. 이러한 효과는 생쥐 뇌에서 GFAP 형광 발현을 감소시켰으며, 이는 반응성 성상세포 매개 신경염증 진행을 저해할 수 있는 가능성을 보였다. 이러한 연구를 통해 파이롭토시스 및 반응성 성상세포 사멸 조절 메커니즘에 대한 새로운 통찰을 제공하며, 추가 연구의 필요성을 제안한다. 대표어 : 별아교세포, 활성별아교세포, 파이롭토시스, 산성 스핑고미엘린 분해효소 

초병렬시퀀싱 방법을 이용한 인간 별아교세포의 microRNA 프로파일링 : MicroRNA Profiling of Human Primary Astrocytes using Massively Parallel Sequencing

김대용 가천의과학대학교 일반대학원 2010 국내석사

Background : Astrocytes have multifunctional properties including structural support for nervous tissue and maintaining metabolic environment. Most primary brain tumors such as astrocytomas and glioblastoma originate from astrocytes. MicroRNAs, a class of non-protein-coding RNAs that are ~22 nucleotides in length, have been implicated in the regulation of various biological processes including apoptosis, animal development, physiological functions such as insulin secretion, and differentiation. Recently, miRNAs have been implicated in cancer as important regulators of tumor suppressor genes and proto-oncogenes. The purpose of this study was to provide the fundamental data for molecular-biological understanding and development of novel diagnosis and therapies of diseases involved with astrocytes by profiling microRNAs of human primary astrocytes. Methods : Human primary astrocytes were prepared from human fetal brains of 12-15 weeks gestation. Astrocytes were purified from other brain cells containing neurons, microglia and oligodendrocytes. Unlike hybridization-based methods, sequencing-based methods allow for direct discovery of novel microRNAs and detection of variations in mature microRNAs. In this study, massively parallel sequencing (MPS) was applied to microRNA profiling of primary human astrocytes. Results : In total, genomic alignments from 32378 sequence reads were annotated as miRNA, piRNA, snRNA, snoRNA, scRNA, scaRNA, tRNA, rRNA, mRNA or unknown based on their genomic position. Among the 721 known human miRNAs registered in miRBase, 260 miRNAs were recovered in primary human astrocytes libraries. In addition, 27 novel miRNA candidates wered identified from unknown clusters of mapped sequence reads. The total set of novel miRNA candidates comprises 27 unique miRNA sequences from introns (12 sequences), intergenic regions (8 sequences), 5’ UTR of protein-coding genes (2 sequences), and 3’ UTR of protein-coding genes (5 sequence). Conclusions : To the best of our knowledge, this presented work is the first to discribe a miRNA profiling in human primary astrocytes using massively parallel sequencing. Our study might be fundamental for the comprehension of the molecular basis of the pathogenesis of such an aggressive tumor as glioblastoma, and give new clues to develop targeted therapies against this still untreatable cancer. Additional studies are now obviously needed to experimentally identify the targets of modulated miRNAs and to correlate them with brain tumor oncogenesis.

Lrp4+ Astrocytes: A Unique Subpopulation Crucial for Blood Vessel Maintenance and Function in the Somatosensory Cortex of Normal and 5xFAD Mice

Arzola, Emily Case Western Reserve University ProQuest Dissertat 2026 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

Astrocytes exhibit significant heterogeneity in morphology, molecular profiles, and function. While these cells perform diverse roles, their functional specialization across distinct subgroups remains poorly characterized. Low-density lipoprotein receptor-related protein 4 (LRP4), a transmembrane receptor critical for agrin signaling for neuromuscular junction (NMJ) formation and maintenance, is selectively expressed in a subset of cortical and hippocampal astrocytes. However, the properties and functions of Lrp4+ astrocytes in the brain remain largely unknown. In this study, we investigated the distribution, morphology, molecular features, and functions of Lrp4+ astrocytes in the cortex. We found that Lrp4+ astrocytes exhibit a unique spatial distribution, predominantly localizing along the pia. Unlike GFAP+ astrocytes, they are GFAP negative and form specialized interactions with blood vessels (BVs), including direct soma-artery contacts, suggesting they represent a distinct astrocyte subtype. Depletion of Lrp4+ astrocytes led to reduced levels of laminin α5, a key extracellular matrix (ECM) protein in the BV basement membrane, accompanied by decreased BV diameter, branching, and density, and impaired cerebral blood flow. Additionally, Lrp4+ astrocyte loss resulted in an increase in GFAP+ astrocytes and IBA1+ microglia. In the 5xFAD mouse model of Alzheimer’s disease (AD), Lrp4+ astrocytes were diminished along the pia and did not associate with amyloid-β (Aβ) plaques, unlike GFAP+ astrocytes. Strikingly, their depletion exacerbated both vascular and Aβ pathology. Supporting these findings, human AD brain samples revealed an inverse correlation between astrocytic Lrp4 and GFAP expression, with no association between Lrp4+ astrocytes and Aβ plaques. Together, our results demonstrate that Lrp4+ astrocytes constitute a specialized subtype distinct from GFAP+ astrocytes, playing a crucial role in maintaining BV basement membrane integrity, vascular structure, and cerebral perfusion. Furthermore, they modulate Aβ pathology, highlighting their potential importance in AD development.

Effects of Korean Red Ginseng- Induced SIRT3 Expression on Mitochondrial Function in Astrocytes : SIRT3-mediated Tom22-HIF-1α pathway

김형수 건국대학교 대학원 2024 국내석사

Astrocytes play a vital role in brain function by supplying energy to neurons. Previous research showed how Korean red ginseng extract (KRGE) can enhance the mitochondrial functions of astrocytes. In adult mouse brain cortex, treating KRGE has shown a boost in hypoxia-inducible factor-1α (HIF- 1α) expression levels and vascular endothelial growth factor (VEGF) expression levels in their astrocytes. VEGF expression is typically regulated by transcription factors like HIF-1α and ERRα. However, KRGE does not seem to influence the expression of ERRα in astrocytes within the mouse brain cortex. Instead, KRGE induces the expression of sirtuin 3 (SIRT3) in astrocytes. SIRT3 is an enzyme that relies on nicotinamide adenine dinucleotide (NAD+) and resides within the mitochondria, contributing to mitochondrial stability. Maintenance of mitochondria requires oxygen, and active mitochondria increase oxygen consumption, potentially leading to hypoxia. The precise relationship between HIF-1α and SIRT3 in KRGE-treated astrocytes regarding mitochondrial function remains unclear. The objective of this study was to investigate how SIRT3 and HIF-1α are interconnected in normoxic astrocytes treated with KRGE. Interestingly, even though ERRα expression remained unaffected, the depletion of SIRT3 through small interfering ribonucleic acid significantly reduced the levels of HIF-1α proteins induced by KRGE in normoxic astrocytes. However, when proline hydroxylase 2 (PHD2) expression was reduced, it resulted in the restoration of HIF-1α protein levels in SIRT3-depleted astrocytes treated with KRGE. The SIRT3-HIF-1α axis appears to regulate the translocation of outer mitochondrial membranes protein such as Tom22 and Tom20, which is activated by KRGE. Consequently, KRGE-induced Tom22 leads to increased oxygen consumption, enhanced mitochondrial membrane potential, and greater stability of HIF-1α through PHD2. In summary, in normoxic astrocytes, KRGE-induced SIRT3 activates the Tom22-HIF-1α pathway by enhancing oxygen consumption, and this occurs independently of ERRα. 성상교세포는 신경세포에 에너지를 공급하여 뇌 기능에 중요한 역할을 한다. 이전 연구에서 홍삼 추출물(KRGE)이 성상교세포의 미토콘드리아 기능을 향상시킬 수 있다는 것이 밝혀졌다. 마우스에 KRGE를 투여하면 성인 마우스 cortex의 성상교세포 내에서 저산소성 유도 인자인 HIF-1α와 혈관내피성장인자(VEGF)의 생성을 유도한다는 것을 확인했다. VEGF 발현은 일반적으로 HIF-1α, ERRα와 같은 전사 인자에 의해 조절된다. 그러나, KRGE는 마우스 cortex 내의 성상교세포에서 ERRα 발현에 영향을 미치지 않았으나,대신 성상교세포에서 KRGE에 의한 SIRT3 발현이 증가함을 확인했다. SIRT3은 NAD 의존성 탈아세틸화 효소로, 미토콘드리아 내에 존재하고 미토콘드리아의 안정성에 기여한다. 미토콘드리아의 유지에는 산소가 필요하며, 활성 미토콘드리아는 산소 소비를 증가시켜 저산소 상태를 유발할 수 있다. 성상교세포에서 KRGE에 의해 유도된 SIRT3와 HIF-1α 매개의 미토콘드리아 기능에 미치는 영향은 아직 명확하지 않기에 이번 연구를 진행하게 되었다. 흥미로운 점은, KRGE를 처리한 성상교세포에 짧은 간섭 RNA(siRNA)로 SIRT3를 감소시키면 ERRα 발현이 영향을 받지 않았지만, KRGE에 의해 유발된 HIF-1α 단백질 수준이 유의적으로 감소했다. 그러나, 위 조건에서 추가로PHD2 단백질의 발현을 억제할 시 HIF-1α 단백질 수준이 회복되는 것을 확인했다. KRGE로 활성화된 SIRT3-HIF-1α 경로에 의해 외부 미토콘드리아 막단백질 Tom22와 Tom20가 조절되었다. 결과적으로, KRGE로 유발된 Tom22는 산소 소비를 증가시키고 미토콘드리아 막 전위를 향상시키며 PHD2를 통해 HIF-1α의 안정성을 증가시킨다. 종합적으로, 정상 상태의 성상교세포에서 KRGE로 유발된 SIRT3가 산소 소비를 향상시킴으로써 Tom22-HIF-1α 경로를 활성화시키며, 이는 ERRα와는 독립적인 별개의 기전이다.

In vitro differentiation of human induced neural stem cells into efficient and functional astrocytes

장아영 고려대학교 대학원 2019 국내석사

Astrocytes participate in various functions such as a guidance for neuronal development and migration during CNS development, an anti-inflammatory cell in neurodegenerative diseases and preservation of blood-brain barrier (BBB) integrity. Recent studies show that astrocytes may be involved in the brain disorders such as Huntington’s disease (HD), Parkinson’s disease (PD) and Alzheimer’s disease (AD), while it remains incompletely explored. In this study, an efficient differentiation protocol for astrocyte was established and pathogenesis of HD was examined in terms of astrocyte dysfunction to identify the correlation of astrocyte and HD. The human induced neural stem cells (hiNSCs) were differentiated into the mature astrocytes with ~90% of high efficiency using our in vitro differentiation protocol, which were expressed with astrocyte markers such as Glial fibrillary acidic protein (GFAP) and S100β. In addition, a functionality of the astrocytes differentiated from the human iNSCs was demonstrated with astrocytic ion channel markers such as Aquaporin 4(AQP4) and Kir4.1, glutamate uptake assays and anti-inflammatory activity. The anti-inflammatory activity was examined by treatment Conditioned Medium (CM) of astrocytes in keratinocyte and expression of inflammatory cytokine including IL-1β, TNFα and IL-6 was identified. Moreover, it was identified the molecular and cellular differences between HD-hiNSC-derived astrocytes and gene corrected hiNSC-derived astrocytes, which reflect the functional loss of astrocytes in HD. Especially, cell death which is the most important factor in HD was compared each other with apoptosis marker; Caspase-3, Annexin V, Bcl-2 and p53. Taken together, these results show that the human iNSCs could be efficiently differentiated into the mature and functional astrocytes, and used to identify the pathogenesis of HD, which suggests that the human iNSC-derived astrocytes may be applied to not only the HD treatments by cell-based transplantation therapy but also the disease modeling cells for the pathological mechanisms of HD in the future.

Critical role of astrocytic MAOB in PTSD, rheumatoid arthritis, and Alzheimer's disease and development of novel therapeutic tools

원우진 KU-KIST Graduate School of Converging Science and 2022 국내박사

Astrocytes are numerically dominant cells in the brain that not only support neurons but also play various pathophysiological roles in the brain. Astrocytes maintain brain homeostasis including regulating the neurotransmitter, releasing growth factors and gliotransmitter, regulating immune response, and regulating ion concentration. Reactive astrocytes, a pathological form of astrocytes, are being reported in various brain disorders and the astrocytes are highlighted as an important cause of disorders. Still, several diseases lack research on the role of astrocytes. Post-traumatic stress disorder (PTSD) is one of the serious neurological disorders that leads to poor quality of life. There are many attempts to treat the symptoms of PTSD, but there is no effective target and pharmacological treatment except anti-depressant drugs. Recently, it has been suggested that the dysfunction of GABA (γ-aminobutyric acid) in the prefrontal cortex is involved in PTSD. My thesis investigated the role and source of GABA in PTSD and reported a unique pathological form of astrocytes called ’stressed astrocytes’ in the prefrontal cortex of PTSD. Moreover, this research demonstrated that aberrant MAOB and ABAT-dependent excessive GABA inhibits the extinction of fear memory. In addition, KDS2010, the MAOB inhibitor, effectively lessens the symptoms of PTSD. Together, this study suggests that astrocytic MAOB is a potent therapeutic target for the treatment of PTSD. Brain inflammation and cognitive impairment have been reported in rheumatoid arthritis (RA) which is a systemic autoimmune disorder. However, the mechanism behind the cognitive impairment in RA is elusive. Previously, it has been reported that reactive astrocytes are critical for memory loss and cognitive impairment in Alzheimer’s disease (AD), known as the neuroinflammatory disease. Regarding this previous idea, my study hypothesized that inflammation-mediated reactive astrocytes induce cognitive impairment in RA. The research reported that aberrant astrocytic MAOB-dependent GABA in the hippocampus induced cognitive impairment. Interestingly, MAOB was not only involved in the cognitive impairment in RA, but it had a pathological role in arthritis. This study demonstrates the MAOB-mediated mechanism in RA and suggests the potential therapeutic target for the treatment of RA. Lastly, it has shown that in addition to the astrocytic MAOB, hydrogen peroxide, which is a byproduct of MAOB, induced the reactive astrocytes and neurodegeneration in AD. Most of the hydrogen peroxide scavengers have problems such as high working concentration of drugs, low blood-brain-barrier permeability, and unexpected pro-oxidant side effects. To overcome these issues, I used KDS12025, that was developed by Dr. Ki Duk Park at Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea, which was a better hydrogen peroxide decomposing drug. Especially, I found that KDS12025 was not working as a direct scavenger of hydrogen peroxide, but as a catalyst that facilitated the endogenous peroxidase activity to decompose hydrogen peroxide. This thesis demonstrated that KDS12025 effectively decomposed hydrogen peroxide and successfully ameliorated the symptoms of AD. Here, I propose KDS12025 as the next therapeutic approach for the treatment of AD. Taken together, my research demonstrates that astrocytic MAOB is involved in PTSD and RA as in other neurological disorders. In addition, these results suggest that KDS2010, a selective and reversible MAOB inhibitor, is a potent therapeutic drug for the treatment of PTSD and RA. Furthermore, my study introduces the novel hydrogen peroxide-decomposing catalyst which treats the symptoms of AD. Altogether, these results also imply that hydrogen peroxide-decomposing catalyst could be the next therapeutic approach for PTSD and RA. I believe that my research contributes to insight into diseases and is socially beneficial.

Effects of Astrocytic Autophagy Modulation on Aβ Pathology and Cognitive Function in Alzheimer’s Disease : Analysis of Astrocytic Autophagy Plasticity and Aβ Clearance Mechanisms

Yeyun Kim 고려대학교 대학원 2026 국내박사

Astrocytes are highly adaptable glial cells that play essential roles in maintaining neuronal homeostasis and protecting the central nervous system from pathological insults. In Alzheimer’s disease (AD), the accumulation of amyloid-beta (Aβ) peptides induces profound cellular stress and promotes the conversion of astrocytes into reactive phenotypes. Although reactive astrocytes are known to participate in neuroinflammatory responses and disease progression, the molecular mechanisms underlying their contribution to Aβ-associated neuropathology remain incompletely understood. Autophagy is a major intracellular degradation pathway responsible for the removal of damaged proteins and organelles, and dysregulation of this pathway has been implicated in several neurodegenerative disorders, including AD. Emerging evidence suggests that astrocytic autophagy may influence extracellular Aβ metabolism; however, the relationship between Aβ-induced proteotoxic stress and autophagic regulation in astrocytes has not been fully elucidated. In this study, we investigated whether exposure to Aβ alters the expression of autophagy-related genes and modulates autophagic flux in astrocytes under pathological conditions associated with AD. Furthermore, we explored how Aβ-responsive autophagy-associated factors contribute to Aβ uptake and clearance in astrocytes using both in vitro systems and an AD mouse model. Our findings provide insight into the dynamic plasticity of astrocytic autophagy during AD progression and suggest that astrocyte-mediated autophagic pathways may represent potential therapeutic targets for enhancing Aβ clearance and alleviating cognitive impairment in Alzheimer’s disease.

Inhibition of telomerase induces senescence in human pluripotent stem cell-derived astrocytes

Seungsoo Oh 고려대학교 대학원 2024 국내석사

성상세포는 뉴런의 생존 및 기능을 돕고 뇌의 항상성을 유지하는 등 중추신경계에서 중요한 역할을 수행하는 교세포이다. 노화된 성상세포는 기능이 저하되어 중추신경계의 기능 장애를 일으킨다고 알려져 있다. 하지만 성상세포의 노화와 관련된 변화들을 재현하는 가용한 인간 체외 모델의 부재는 뇌의 노화에 대한 기전 및 치료법을 연구하는 데 제한이 된다. 본 연구는 텔로머레이즈 억제제 BIBR1532를 사용하여 텔로미어 단축을 가속화함으로써 인간 전분화능 줄기세포로부터 노화 표현형을 보이는 성상세포를 신속하게 분화시키는 방법을 제안했다. 이러한 노화된 성상세포에서는 짧아진 텔로미어, 감소한 증식 및 독특한 형태가 관찰되었다. 또한 DNA 및 핵 손상의 증거와 함께 다양한 노화 관련 형질도 확인되었다. 흥미롭게도 BIBR1532를 사용해 분화된 성상세포는 일부의 노화 연관 분비 표현형만을 나타냈으며, 이는 GATA4에 의해 조절되는 IL-1α의 작용에 의한 것으로 보인다. 더불어 전통적인 성상세포와 기능적으로 유사함을 유지하면서 반응성을 나타내어, BIBR1532를 처리한 인간 전분화능 줄기세포 유래 성상세포가 노화된 성상세포에 대한 다양한 연구에 유용한 모델로 기능할 수 있음을 시사한다. 따라서 본 연구 결과는 텔로미어 단축에 의해 유도된 노화된 성상세포의 특성을 명확히하면서 노화된 뇌의 연구에 사용 가능한 인간 체외 세포 모델을 제공한다. Astrocytes are glial cells that play a crucial role in the central nervous system (CNS), supporting the survival and function of neurons and maintaining brain homeostasis. Aging astrocytes are known to undergo functional decline, leading to CNS dysfunction, and are implicated in the progression of various neurodegenerative diseases. However, the lack of an available human in vitro model for recapitulating age-related changes of astrocytes represents a limitation for studying the mechanisms and therapies for aging brain. This study proposed a method to rapidly differentiate astrocytes exhibiting an aging phenotype from human pluripotent stem cells (hPSCs) by accelerating telomere shortening using the telomerase inhibitor BIBR1532. In these aging astrocytes, shortened telomeres, decreased proliferation, and distinct morphology were observed. Evidence of DNA and nuclear damage was also confirmed, along with various aging-related phenotypes. Interestingly, astrocytes differentiated using BIBR1532 expressed only some components of the senescence-associated secretory phenotype (SASP), likely mediated by the action of IL-1α regulated by GATA4. Additionally, these cells maintained functional similarity to conventional astrocytes, while exhibiting their reactivity, suggesting that hPSC-derived astrocytes treated with BIBR1532 could serve as a useful model for diverse studies on aging astrocytes. Therefore, the findings of this study not only elucidate the characteristics of aging astrocytes induced by telomere shortening but also provide a human in vitro cellular model for studying the aging brain.