Promotion of astrocyte-neuron glutamate-glutamine shuttle by SCFA contributes to the alleviation of Alzheimer's disease
Yan Sun,
Huaiwu Zhang,
Xuan Zhang,
Wenzhao Wang,
Yong Chen,
Zhiyou Cai,
Qihui Wang,
Jun Wang,
Yi Shi
Affiliations
Yan Sun
Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China; CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
Huaiwu Zhang
Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China; CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
Xuan Zhang
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
Wenzhao Wang
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
Yong Chen
Beijing Life Science Academy (BLSA), Beijing, China
Zhiyou Cai
Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China
Qihui Wang
Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China; CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China; Corresponding author. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Jun Wang
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China; Corresponding author.
Yi Shi
Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China; CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China; Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China; Center for Influenza Rsearch and Early-Warning (CASCIRE), CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID), Chinese Academy of Sciences, Beijing, China; Beijing Life Science Academy (BLSA), Beijing, China; Corresponding author. Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.
The brain is particularly susceptible to oxidative damage which is a key feature of several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease. The shuttling of glutathione (GSH) precursors from astrocytes to neurons has been shown to be instrumental for the neuroprotective activity. Here, we revealed that short chain fatty acids (SCFA), which have been related to AD and PD, could promote glutamate-glutamine shuttle to potentially resist oxidative damage in neurons at cellular level. Furthermore, we performed nine-month-long dietary SCFA supplementations in APPswe/PS1dE9 (APP/PS1) mice, and showed that it reshaped the homeostasis of microbiota and alleviated the cognitive impairment by reducing Aβ deposition and tau hyperphosphorylation. Single-cell RNA sequencing analysis of the hippocampus revealed SCFA can enhance astrocyte-neuron communication including glutamate-glutamine shuttle, mainly by acting on astrocyte in vivo. Collectively, our findings indicate that long-term dietary SCFA supplementations at early aging stage can regulate the neuroenergetics to alleviate AD, providing a promising direction for the development of new AD drug.
