Gut-brain axis in Alzheimer's disease: translational 7T MRI markers and underlying mechanisms

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Project Summary Alzheimer’s disease (AD) is the most common form of dementia with hallmarks of extracellular beta amyloid (Aβ) plaques (A), intraneuronal tau tangles (T), and neurodegeneration (N), known as the A/T/N framework, a descriptive classification for AD biomarkers. Accumulating evidence shows that a severely imbalanced microbial community, or dysbiosis, is associated with A/T/N and neuroinflammation in AD patients compared with healthy controls (HC). However, it remains unknown how individual microbiota correlates with regional A/T/N neuroimaging markers in AD and HC. It is also unknown if dysbiosis directly promotes and accelerates A/T/N at early stage and whether there are effective interventions available to mitigate the dysbiosis and thus AD risk. Therefore, the goal of the project is to design a translational study, employing parallel human and preclinical animal experiments to understand mechanism and identify interventions for filling these knowledge gaps. The central hypothesis is that severity of dysbiosis between AD and HC individuals will correlate with their regional A/T/N imaging markers and cognitive status; young healthy triple transgenic AD (3xTg-AD) mice received fecal microbiome transplantation (FMT) from AD patients (FMT-AD) will have reproduced dysbiosis as the donors, which will accelerate A/T/N, neuroinflammation and cognitive impairment of the mice. Interventions with inducible nitric oxide synthase (iNOS) inhibition will mitigate A/T/N and neuroinflammation, and prebiotic diet (inulin) supplementation can further restore microbiome balance to protect brain physiology and cognition. The central hypothesis will be tested by the following three Specific Aims: (1) Identify correlation of dysbiosis, A/T/N imaging markers and cognition in humans; (2) Reveal impact of iNOS on mitigating A/T/N in the presence of dysbiosis; (3) Determine ability of inulin, with and without functional iNOS, to rescue FMT-AD- induced A/T/N and cognitive impairment. Participants who had PET scans for “A/T” will be recruited for the study, and ultrahigh resolution 7T MRI will be used to determine “N”. Translational 7T MRI, gut microbiome sequencing and cognitive assessments will be applied to both humans and mice to determine longitudinal effects of gut-brain interactions. A novel iNOS knockout triple transgenic AD (iNOS-KO/3xTg-AD) mouse model has been created for the project to study the iNOS effects on mitigating A/T/N despite of gut dysbiosis. Biochemical assays and brain staining will be used to determine “A/T” in the mice. Inflammatory gene expression will be identified by transcriptomics. It is anticipated that the findings from this study will have tremendous positive impact as they will enhance the understanding of gut-brain interactions underlying A/T/N in AD and pave the way for future disease-modifying interventions for AD via the microbiome-gut-brain axis. As iNOS inhibitors, inulin diet, 7T MRI and microbiome analyses are available for humans, the success of animal interventional outcomes and the human study pipeline established in the study may pave a way for future clinical trials to mitigate AD risk by gut microbiome modulation.