Characterising dysbiosis in Alzheimer’s disease utilising the APP/PS1 mouse model

Finn, Nicole (2018) Characterising dysbiosis in Alzheimer’s disease utilising the APP/PS1 mouse model. Masters thesis, UNSPECIFIED.

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Abstract

The gut brain axis (GBA) is a bi-directional communication system between the gastrointestinal tract (GI) and the brain. Correct functioning of the GBA is essential to human health and its dysfunction has been widely implicated in a variety of diseases including, irritable bowel syndrome (IBS), Parkinson’s disease (PD), anxiety, depression, and more recently Alzheimer’s disease (AD). Pathological changes associated with GBA dysfunction include: increased permeability of the epithelial gut barrier, localised and systemic inflammation, increased permeability of the blood brain barrier (BBB), insulin resistance and alterations in the production of microbial metabolites. In our laboratory, we utilised the APP/PS1 transgenic mouse as a model for cerebral amyloidosis in the brain. These mice overproduce β-amyloid (Aβ), allowing the study of mechanisms of neuropathology. In this project we used seven and fifteen-month mice as a representation of early and late Aβ plaque deposition. Histological examination of tissue architecture in addition to goblet cell and enteroendocrine cell (EEC) counts were performed. Mucosal and luminal bacterial community profiling was assessed through quantitative real-time PCR (qRT-PCR) and denaturing gel gradient electrophoresis (DGGE). There was a significant decrease in the phylum Firmicutes and number of EEC’s in the colon of seven-month APP/PS1 mice compared to WT littermates. By fifteen-months the dysbiosis had recovered, however there was a decrease in goblet cells in the villi and crypts of the ileum. A three-month age group was introduced which was found to have a significant difference in the mucosal- associated microbiota in the caecum of APP/PS1 mice. The dysbiosis was accompanied by a significant decrease in crypt depth and an increase in EEC numbers in the colon. The results suggest that dysbiosis in the large intestine occurs in early neuropathology and is normalised by late AD pathology. We propose that dysbiosis induces changes in the tissue architecture and cell population numbers during the progression of pathology, which exacerbates GBA dysfunction. The potential for this research lies with the possibility of identifying an AD microbiota profile, which could make it possible to identify high-risk individuals by comparing profiles. Altering the microbiota through the use of probiotics or changing certain lifestyle factors such as adopting a Mediterranean diet, may reduce the likelihood of a high-risk person developing or slow down the progression of AD.

Item Type:
Thesis (Masters)
ID Code:
129812
Deposited By:
Deposited On:
18 Dec 2018 11:03
Refereed?:
No
Published?:
Published
Last Modified:
17 Sep 2020 07:02