Gut microbiota regulate cognitive deficits and amyloid deposition in a model of Alzheimer’s disease

• Published in: Journal of neurochemistry 2020-11, Vol.155 (4), p.448-461
• Main Authors: Li, Zhuo, Zhu, Hua, Guo, Yaxi, Du, Xiaopeng, Qin, Chuan
• Format: Article
• Language: English
• Subjects: 16S rRNA sequence; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - psychology; Alzheimer's disease; Amyloid beta-Protein Precursor - metabolism; amyloid deposition; Amyloid precursor protein; Animals; Cognition; Cognition Disorders - metabolism; Cognition Disorders - pathology; Cognition Disorders - psychology; Cognitive ability; Deposition; Digestive system; Disease Models, Animal; Female; Gastrointestinal Microbiome - physiology; Gastrointestinal tract; Gene expression; Gene sequencing; gut microbiota; Intestinal microflora; Intestine; MAP kinase; memory; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microbiomes; Microbiota; Neurodegenerative diseases; Pathogenesis; Ribonucleic acid; RNA; rRNA 16S; Signal transduction; Signaling; transcriptome sequencing; Transgenic mice
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15031

Gut microbiota, comprising a vast number of microorganism species with complex metagenome, are known to be associated with Alzheimer's disease (AD) and amyloid deposition. However, studies related to gut microbiota have been mostly restricted to comparisons of amyloid deposits, while investigations on neurobehavioral changes and the pathogenesis of AD are limited. Therefore, we aimed to identify the relationship between changes in the intestinal microbiome and the pathogenesis of AD. APPswe/PS1ΔE9 (PAP) transgenic mice and wild‐type (WT) mice of different age groups were used. The composition of intestinal bacterial communities in the mice was determined by 16S ribosomal RNA sequencing (16S rRNA Seq), and the Y maze was used to measure cognitive function. Transcriptome sequencing (RNA Seq) and Gene Expression Omnibus (GEO) database (GSE 36980) were used to filter differentially expressed genes (DEGs) between specific pathogen‐free (SPF) and germ‐free (GF) mice. Quantitative reverse‐transcriptase PCR (qRT‐PCR) and western blot (WB) were used to verify the results. We found that the intestinal microbiota was significantly different between 5‐month‐old PAP and WT mice and the cognition of SPF PAP mice was diminished compared to GF PAP and SPF WT mice. DEGs in 5‐month‐old SPF and GF mice were enriched in the MAPK signalling pathway, and expression of amyloid precursor protein and amyloid deposition increased in 5‐month‐old SPF PAP mice. Results from this study showed that changes in intestinal microbiota were correlated with impairment of cognitive function and might promote amyloid deposition by stimulating the MAPK signalling pathway in the brain. This study showed that signals from gut microbes were required for the neuroinflammatory responses and cognitive deficits in a mouse model of Alzheimer's disease. A clear association was established between changes in intestinal microbiota in APPswe/PS1ΔE9 transgenic mice and amyloid deposition via the activation of the MAPK signalling pathway, confirmed by 16S rRNA sequencing and transcriptome analysis. We believe that these findings will have direct implications in the development of methods that can exploit gut microbiota to control amyloid deposition, and thus alleviate neuroinflammation and provide clinical benefits in patients with Alzheimer's disease.