한빛사논문
- 조회415
Suhyun Kim1†, Heejung Chun2†, Yunha Kim1†, Yeyun Kim1,3, Uiyeol Park1,4, Jiyeon Chu1,3, Mridula Bhalla5,6, Seung-Hye Choi7, Ali Yousefian-Jazi1, Sojung Kim1,3, Seung Jae Hyeon1, Seungchan Kim1, Yeonseo Kim8, Yeon Ha Ju5,6, Seung Eun Lee9, Hyunbeom Lee8, Kyungeun Lee10, Soo-Jin Oh1, Eun Mi Hwang11, Junghee Lee12,13*, C. Justin Lee5,6* and Hoon Ryu1,14*
1K-Laboratory, Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
2College of Pharmacy, Yonsei-SL Bigen Institute (YSLI), Yonsei University, Incheon 21983, Republic of Korea
3Department of Integrated Biomedical and Life Science, Graduate School, Korea University, Seoul 02841, Republic of Korea
4Deaprtment of Medicine, Hanyang University Medical School, Seoul 04763, Republic of Korea
5Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon 34126, Republic of Korea
6IBS School, University of Science and Technology (UST), Daejeon 34113, Republic of Korea
7Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
8Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
9Research Animal Resource Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
10Advanced Analysis and Data Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
11Center for Brain Function, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
12Department of Neurology, Boston University Alzheimer’s Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA
13VA Boston Healthcare System, Boston, MA 02130, USA
14Department of Converging Science and Technology, KHU-KIST, Kyung Hee University, Seoul 02447, Republic of Korea
†Suhyun Kim, Heejung Chun and Yunha Kim contributed equally to this work.
*Correspondence: Junghee Lee, C. Justin Lee, Hoon Ryu
Abstract
Background: Astrocytes, one of the most resilient cells in the brain, transform into reactive astrocytes in response to toxic proteins such as amyloid beta (Aβ) in Alzheimer's disease (AD). However, reactive astrocyte-mediated non-cell autonomous neuropathological mechanism is not fully understood yet. We aimed our study to find out whether Aβ-induced proteotoxic stress affects the expression of autophagy genes and the modulation of autophagic flux in astrocytes, and if yes, how Aβ-induced autophagy-associated genes are involved Aβ clearance in astrocytes of animal model of AD.
Methods: Whole RNA sequencing (RNA-seq) was performed to detect gene expression patterns in Aβ-treated human astrocytes in a time-dependent manner. To verify the role of astrocytic autophagy in an AD mouse model, we developed AAVs expressing shRNAs for MAP1LC3B/LC3B (LC3B) and Sequestosome1 (SQSTM1) based on AAV-R-CREon vector, which is a Cre recombinase-dependent gene-silencing system. Also, the effect of astrocyte-specific overexpression of LC3B on the neuropathology in AD (APP/PS1) mice was determined. Neuropathological alterations of AD mice with astrocytic autophagy dysfunction were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through novel object recognition test (NOR) and novel object place recognition test (NOPR).
Results: Here, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Aβ. Aβ transiently induces expression of LC3B gene and turns on a prolonged transcription of SQSTM1 gene. The Aβ-induced astrocytic autophagy accelerates urea cycle and putrescine degradation pathway. Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Astrocyte-specific knockdown of LC3B and SQSTM1 significantly increases Aβ plaque formation and GFAP-positive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal marker and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Aβ aggregates in the brain of APP/PS1 mice. An increase of LC3B and SQSTM1 protein is found in astrocytes of the hippocampus in AD patients.
Conclusions: Taken together, our data indicates that Aβ-induced astrocytic autophagic plasticity is an important cellular event to modulate Aβ clearance and maintain cognitive function in AD mice.
논문정보
- Research article
- 2024년 07월 (BRIC 등록일 2024-07-24)
- 국내(교신)+국외 연구진
- 생명과학 > 세포생물학
관련 보도자료
- Bio통신원
- 2024. 08. 26
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