Microbes and the ageing brain: do host-microbe interactions accelerate age-related cognitive decline?

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Rationale: A hallmark of the aging brain is the deposition of amyloid-Beta (ABeta). Elderly with chronic microbial infections have a higher amyloid load and an increased risk of developing dementia, but the underlying mechanism(s) are not known. ABeta -peptides share physiochemical and biological activities with antimicrobial peptides. For example, ABeta protects cultured cells against lethal yeast and bacterial infections, and sequesters pathogens during the process of ABeta fibrilization. We hypothesize that pathogen-mediated ABeta fibrilization is part of the innate immune response, which undergoes chronic activation during aging leading to excessive ABeta deposition and neural dysfunction that eventually results in dementia. Approaches to be used: We will use in vivo models (mouse and C. elegans), to test how microbial infections such as Salmonella Typhimurium, Candida albicans and Porphyromonas gingivalis affect healthy ageing, by performing an array of behavioural, physiological and cellular assays, including neuronal function, gut permeability, microbiome composition and immune responses. The student will have access to transgenic models to test the hypothesis that microbial infections accelerate the ageing process in the presence of aggregated human amyloid. The student will also use a range of pharmacological and/or dietary approaches, to interfere with host-microbe interaction with the aim to promote healthy ageing and delay neuronal dysfunction. These interventions will be tested in C. elegans and confirmed in mouse models. Areas of impact: Taking into consideration the strong links between microbial pathogens and brain dysfunction and the emergence of the antimicrobial hypothesis of dementia, this studentship may provide much needed insight into the mechanisms underpinning neurodegeneration associated with microbial pathogens. Establishing the mechanisms by which microbial pathogens impact on the neurons in or outside the brain, may inform aspects of future translational studies, including discovery of candidate therapeutics aimed at regulating pathogen-associated networks and molecules in dementia.