Gut dysbiosis aggravates cognitive deficits,amyloid pathology and lipid metabolism dysregulation in a transgenic mouse model of Alzheimer's disease  

作　　者：Chang Qu Qing-Qing Xu Wen Yang Mei Zhong Qiuju Yuan Yan-Fang Xian Zhi-Xiu Lin 

机构地区：[1]School of Chinese Medicine,Faculty of Medicine,The Chinese University of Hong Kong,Hong Kong,China [2]College of Forestry and Landscape Architecture,South China Agricultural University,Guangzhou,510640,China [3]Centre for Regenerative Medicine and Health,Hong Kong Institute of Science&Innovation,Chinese Academy of Sciences,Hong Kong Science Park,Shatin,N.T.,Hong Kong,China [4]Hong Kong Institute of Integrative Medicine,The Chinese University of Hong Kong,Hong Kong,China

出　　处：《Journal of Pharmaceutical Analysis》2023年第12期1526-1547,共22页药物分析学报（英文版）

基　　金：This work was partially supported by National Natural Science Foundation of China(Project No.:82104414);Natural Science Foundation of Guangdong Province of China(Project No.:2022A1515011682);a direct grant from The Chinese University of Hong Kong(Project No.:2021.071).

摘　　要：Gut dysbiosis,a well-known risk factor to triggers the progression of Alzheimer's disease(AD),is strongly associated with metabolic disturbance.Trimethylamine N-oxide(TMAO),produced in the dietary choline metabolism,has been found to accelerate neurodegeneration in AD pathology.In this study,the cognitive function and gut microbiota of TgCRND8(Tg)mice of different ages were evaluated by Morris water maze task(MWMT)and 16S rRNA sequencing,respectively.Young pseudo germ-free(PGF)Tg mice that received faecal microbiota transplants from aged Tg mice and wild-type(WT)mice were selected to determine the role of the gut microbiota in the process of neuropathology.Excessive choline treatment for Tg mice was used to investigate the role of abnormal choline metabolism on the cognitive functions.Our results showed that gut dysbiosis,neuroinflammation response,Ab deposition,tau hyperphosphorylation,TMAO overproduction and cyclin-dependent kinase 5(CDK5)/transcription 3(STAT3)activation occurred in Tg mice age-dependently.Disordered microbiota of aged Tg mice accelerated AD pathology in young Tg mice,with the activation of CDK5/STAT3 signaling in the brains.On the contrary,faecal microbiota transplantation from WT mice alleviated the cognitive deficits,attenuated neuroinflammation,Ab deposition,tau hyperphosphorylation,TMAO overproduction and suppressed CDK5/STAT3 pathway activation in Tg mice.Moreover,excessive choline treatment was also shown to aggravate the cognitive deficits,Ab deposition,neuroinflammation and CDK5/STAT3 pathway activation.These findings provide a novel insight into the interaction between gut dysbiosis and AD progression,clarifying the important roles of gut microbiota-derived substances such as TMAO in AD neuropathology.

关 键 词：Alzheimer's disease Gut dysbiosis NEUROPATHOLOGY TgCRND8 mice 

分 类 号：R749.16[医药卫生—神经病学与精神病学]