Visualizing reactive astrocyte-neuron interaction in Alzheimer’s disease using 11C-acetate and 18F-FDG.

Apr 17, 2023

Experts: Min-Ho Nam,Hae Young Ko,Dongwoo Kim,Sangwon Lee,Yongmin Mason Park,Seung Jae Hyeon,Woojin Won,Jee-In Chung,Seon Yoo Kim,Han Hee Jo,Kyeong Taek Oh,Young-Eun Han,Gwan-Ho Lee,Yeon Ha Ju,Hyowon Lee,Hyunjin Kim,Jaejun Heo,Mridula Bhalla,Ki Jung Kim,Jea Kwon,Thor D Stein,Mingyu Kong,Hyunbeom Lee,Seung Eun Lee,Soo-Jin Oh,Joong-Hyun Chun,Mi-Ae Park,Ki Duk Park,Hoon Ryu,Mijin Yun,C Justin Lee

Reactive astrogliosis is a hallmark of Alzheimer’s disease (AD). However, a clinically validated neuroimaging probe to visualize the reactive astrogliosis is yet to be discovered. Here, we show that PET imaging with 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. To investigate the alterations of acetate and glucose metabolism in the diseased brains and their impact on the AD pathology, we adopted multifaceted approaches including microPET imaging, autoradiography, immunohistochemistry, metabolomics, and electrophysiology. Two AD rodent models, APP/PS1 and 5xFAD transgenic mice, one adenovirus-induced rat model of reactive astrogliosis, and post-mortem human brain tissues were used in this study. We further curated a proof-of-concept human study that included 11C-acetate and 18F-FDG PET imaging analyses along with neuropsychological assessments from 11 AD patients and 10 healthy control subjects. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1) in rodent models of both reactive astrogliosis and AD. The elevated acetate uptake is associated with reactive astrogliosis and boosts the aberrant astrocytic GABA synthesis when amyloid-β is present. The excessive astrocytic GABA subsequently suppresses neuronal activity, which could lead to glucose uptake through decreased glucose transporter-3 in the diseased brains. We further demonstrate that 11C-acetate uptake was significantly increased in the entorhinal cortex, hippocampus and temporo-parietal neocortex of the AD patients compared to the healthy controls, while 18F-FDG uptake was significantly reduced in the same regions. Additionally, we discover a strong correlation between the patients’ cognitive function and the PET signals of both 11C-acetate and 18F-FDG. We demonstrate the potential value of PET imaging with 11C-acetate and 18F-FDG by visualizing reactive astrogliosis and the associated neuronal glucose hypometablosim for AD patients. Our findings further suggest that the acetate-boosted reactive astrocyte-neuron interaction could contribute to the cognitive decline in AD.
© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author

admin

View all posts

ABOUT THE EXPERTS

Min-Ho Nam,Hae Young Ko,Dongwoo Kim,Sangwon Lee,Yongmin Mason Park,Seung Jae Hyeon,Woojin Won,Jee-In Chung,Seon Yoo Kim,Han Hee Jo,Kyeong Taek Oh,Young-Eun Han,Gwan-Ho Lee,Yeon Ha Ju,Hyowon Lee,Hyunjin Kim,Jaejun Heo,Mridula Bhalla,Ki Jung Kim,Jea Kwon,Thor D Stein,Mingyu Kong,Hyunbeom Lee,Seung Eun Lee,Soo-Jin Oh,Joong-Hyun Chun,Mi-Ae Park,Ki Duk Park,Hoon Ryu,Mijin Yun,C Justin Lee

Min-Ho Nam

Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.

Department of KHU-KIST Convergence Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea.

Hae Young Ko

Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.

Dongwoo Kim

Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.

Sangwon Lee

Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.

Yongmin Mason Park

Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Republic of Korea.

IBS School, University of Science and Technology, Daejeon 34126, Republic of Korea.

Seung Jae Hyeon

Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.

Woojin Won

Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Republic of Korea.

Jee-In Chung

Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.

Seon Yoo Kim

Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.

Han Hee Jo

Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.

Kyeong Taek Oh

Department of Medical Engineering, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.

Young-Eun Han

Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.

Gwan-Ho Lee

Research Resources Division, KIST, Seoul 02792, Republic of Korea.

Yeon Ha Ju

Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.

Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Republic of Korea.

IBS School, University of Science and Technology, Daejeon 34126, Republic of Korea.

Hyowon Lee

Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.

Hyunjin Kim

Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.

Department of KHU-KIST Convergence Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea.

Jaejun Heo

Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.

Mridula Bhalla

Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Republic of Korea.

IBS School, University of Science and Technology, Daejeon 34126, Republic of Korea.

Ki Jung Kim

Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Republic of Korea.

Jea Kwon

Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Republic of Korea.

Thor D Stein

Boston University Alzheimer’s Disease Research Center and Department of Pathology, Chobanian and Avedisian Boston University School of Medicine, Boston, MA 02130, USA.

Mingyu Kong

Molecular Recognition Research Center, KIST, Seoul 02792, Republic of Korea.

Hyunbeom Lee

Molecular Recognition Research Center, KIST, Seoul 02792, Republic of Korea.

Seung Eun Lee

Research Resources Division, KIST, Seoul 02792, Republic of Korea.

Soo-Jin Oh

Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.

Joong-Hyun Chun

Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.

Mi-Ae Park

Department of Radiology, UT Southwestern Medical Center, Dallas, TX 75390, USA.

Ki Duk Park

Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.

Hoon Ryu

Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.

Boston University Alzheimer’s Disease Research Center and Department of Pathology, Chobanian and Avedisian Boston University School of Medicine, Boston, MA 02130, USA.

Mijin Yun

Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.

C Justin Lee

Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Republic of Korea.

IBS School, University of Science and Technology, Daejeon 34126, Republic of Korea.