Scutellarin Modulates the Microbiota-Gut-Brain Axis and Improves Cognitive Impairment in APP/PS1 Mice

Article type: Research Article

Authors: Zhang, Shujuan^{a; b} | Wei, Dongfeng^{d; e} | Lv, Shuang^b | Wang, Lei^b | An, Haiting^{c; e} | Shao, Wen^b | Wang, Yun^{c; e} | Huang, Yaping^b | Peng, Dantao^{b; *} | Zhang, Zhanjun^{c; e; *}

Affiliations: [a] Department of Rehabilitation Medicine, Xuan Wu Hospital, Capital Medical University, Beijing, China | [b] Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China Department of Neurology, China-Japan Friendship Hospital, Chaoyang District, Beijing, China | [c] State Key Laboratory of Cognitive Neuroscience and Learning and IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China | [d] Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China | [e] BABRI Center, Beijing Normal University, Beijing, China

Correspondence: [*] Correspondence to: Dantao Peng, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, 100029, China; Department of Neurology, China-Japan Friendship Hospital, 2 Yinghuayuan East Street, Chaoyang District, Beijing 100029, China. E-mail: [email protected]. and Zhanjun Zhang, State Key Laboratory of Cognitive Neuroscience and Learning and IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing 100875, China. E-mail: [email protected].

Abstract: Background:Scutellarin, a flavonoid purified from the Chinese herb Erigeron breviscapus, has been reported to prevent Alzheimer’s disease (AD) by affecting Aβ assembly. Given the low brain uptake rate of scutellarin, we hypothesize that the microbiota-gut-brain axis may be a potential route by which scutellarin prevents AD. Objective:This study aimed to explore the microbiota-gut-brain mechanism by which scutellarin prevented AD. Methods:Scutellarin was administrated to APP/PS1 mouse model of AD for two months, and the behaviors, pathological changes as well as gut microbial changes in APP/PS1 mice were evaluated after scutellarin treatment. Results:This study found that scutellarin improved Aβ pathology, neuroinflammation, and cognitive deficits in APP/PS1 mice. It elucidated the effects of scutellarin on the diversity and activity of gut microbiota in APP/PS1 mice and these findings promoted us to focus on inflammation-related bacteria and short-chain fatty acids (SCFAs). Cognitive behaviors were significantly associated with inflammatory cytokines and inflammation-related bacteria, suggesting that microbiota-gut-brain axis was involved in this model and that inflammatory pathway played a crucial role in this axis. Moreover, we observed that cAMP-PKA-CREB-HDAC3 pathway downstream of SCFAs was activated in microglia of AD and inactivated by scutellarin. Furthermore, by chromatin immunoprecipitation (ChIP) assays, we found that the increased association between acetylated histone 3 and interleukin-1β (IL-1β) promoter in AD mice was reversed by scutellarin, leading to a decreased level of IL-1β in scutellarin-treated AD mice. Conclusion:Scutellarin reverses neuroinflammation and cognitive impairment in APP/PS1 mice via beneficial regulation of gut microbiota and cAMP-PKA-CREB-HDAC3 signaling in microglia.

Keywords: Alzheimer’s disease, cAMP-response element binding protein (CREB), cyclic adenosine monophosphate (cAMP), gut microbiota, histone deacetylase, interleukin, protein kinase, scutellarin

DOI: 10.3233/JAD-220532

Journal: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 955-975, 2022