Project No. 2382
Dr Murphy Wan – University of Portsmouth
Prof Jerome Swinny – University of Portsmouth
Prof Louise Serpell – University of Sussex
Compelling evidence indicates that disturbances along the microbiota-gut-brain (MGB) axis significantly contribute to the pathogenesis of Alzheimer’s disease (AD).
However, the precise molecular mechanisms remain unresolved. Our supporting data identify an extensive amyloid precursor protein (APP)-amyloid β (Aβ) system within the enteric nervous system of the mouse gut. Furthermore, recent work from other groups have shown that Aβ has antibacterial effects. This raises the prospect that perturbations of the local GI APP-Aβ system, and changes in GI Aβ production, could alter the composition of GI bacteria, resulting in dysbiosis. This is important because dysbiosis is contributes to the production of immuno-modulating metabolites which induce systemic inflammation and blood-brain barrier impairment. This in turn affects the brain clearance of AD pathology, exacerbating the disease spectrum.
The aims of this study are to determine the effect of GI microbiome on the APP-Aβ system using combined metagenomics-metabolomics approach in the APP-PSEN1 mouse model which over-expresses APP, resulting in increased Aβ production. The molecular effects of GI bacterial metabolites and Aβ peptides on neuroinflammation will also be examined by different cell based assays (confocal microscopy, cytotoxicity assays, RNAseq) using human neuroblastoma cells and mouse primary cortical neurons.
This project involves multidisciplinary approaches and supervision. Integration of different OMICS technologies (RNAseq, metagenomics and metabolomics) with the use of systems biology will allow the better understanding of the cellular and molecular basis of MGB axis in the pathogeneis of AD and potentially identifying novel biomarkers for disease pathogenesis and treatment.
The ideal candidate should have a strong interest in neuroscience, microbiology and biochemistry. He/she should be keen to adopt cross-interdisciplinary approaches to address complex problems and have excellent interpersonal skills for working with collaborators across different research disciplines.