AUTHOR=Yan Yuqing , Gao Ye , Fang Qingli , Zhang Nianping , Kumar Gajendra , Yan Hailong , Song Lijuan , Li Jiehui , Zhang Yuna , Sun Jingxian , Wang Jiawei , Zhao Linhu , Skaggs Keith , Zhang Han-Ting , Ma Cun-Gen 

TITLE=Inhibition of Rho Kinase by Fasudil Ameliorates Cognition Impairment in APP/PS1 Transgenic Mice via Modulation of Gut Microbiota and Metabolites

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=13

YEAR=2021

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2021.755164

DOI=10.3389/fnagi.2021.755164

ISSN=1663-4365

ABSTRACT=<p><bold>Background:</bold> Fasudil, a Rho kinase inhibitor, exerts therapeutic effects in a mouse model of Alzheimer's disease (AD), a chronic neurodegenerative disease with progressive loss of memory. However, the mechanisms remain unclear. In addition, the gut microbiota and its metabolites have been implicated in AD.</p><p><bold>Methods:</bold> We examined the effect of fasudil on learning and memory using the Morris water-maze (MWM) test in APPswe/PSEN1dE9 transgenic (APP/PS1) mice (8 months old) treated (i.p.) with fasudil (25 mg/kg/day; ADF) or saline (ADNS) and in age- and gender-matched wild-type (WT) mice. Fecal metagenomics and metabolites were performed to identify novel biomarkers of AD and elucidate the mechanisms of fasudil induced beneficial effects in AD mice.</p><p><bold>Results:</bold> The MWM test showed significant improvement of spatial memory in APP/PS1 mice treated with fasudil as compared to ADNS. The metagenomic analysis revealed the abundance of the dominant phyla in all the three groups, including <italic>Bacteroidetes</italic> (23.7–44%) and <italic>Firmicutes</italic> (6.4–26.6%), and the increased relative abundance ratio of <italic>Firmicutes</italic>/<italic>Bacteroidetes</italic> in ADNS (59.1%) compared to WT (31.7%). In contrast, the <italic>Firmicutes</italic>/<italic>Bacteroidetes</italic> ratio was decreased to the WT level in ADF (32.8%). Lefse analysis of metagenomics identified <italic>s_Prevotella_sp_CAG873</italic> as an ADF potential biomarker, while <italic>s_Helicobacter_typhlonius</italic> and <italic>s_Helicobacter_sp_MIT_03-1616</italic> as ADNS potential biomarkers. Metabolite analysis revealed the increment of various metabolites, including glutamate, hypoxanthine, thymine, hexanoyl-CoA, and leukotriene, which were relative to ADNS or ADF microbiota potential biomarkers and mainly involved in the metabolism of nucleotide, lipids and sugars, and the inflammatory pathway.</p><p><bold>Conclusions:</bold> Memory deficit in APP/PS1 mice was correlated with the gut microbiome and metabolite status. Fasudil reversed the abnormal gut microbiota and subsequently regulated the related metabolisms to normal in the AD mice. It is believed that fasudil can be a novel strategy for the treatment of AD via remodeling of the gut microbiota and metabolites. The novel results also provide valuable references for the use of gut microbiota and metabolites as diagnostic biomarkers and/or therapeutic targets in clinical studies of AD.</p>