Abstract
Recent discoveries have overturned the long-standing belief that the brain is an immune-privileged organ, unaffected by peripheral immunity. Epidemiological and preclinical evidence suggest that the risk of developing Alzheimer's Disease (AD) can be exacerbated by inflammation in the gut. I hypothesize that gut-derived amyloids, produced by the enteric microbiome but also by the host as part of an innate immune response, may promote neurodegeneration by activating the brain's immune system. Therefore, I aim to dissect the mechanisms with which these peripherally generated amyloids influence central neuroinflammation and contribute to AD pathology. First, I will map the changes in the brain's immune cell composition after intraperitoneal injection of the bacterial amyloid curli and compare it to Dextran Sulphate Sodium (DSS)-induced colitis, a condition that triggers production of host-derived Serum Amyloid A (SAA). Next, I will analyse the amyloid-induced neuro-immune signalling pathways using an in vitro co-culture of human enteric glia and microglia-containing neurospheres. Finally, I will assess the impact of peripheral inflammation on amyloidosis progression in a mouse model of AD and evaluate the clinical relevance of my findings in AD patient samples. By uncovering the early immune-driven mechanisms underlying AD pathogenesis, my work will provide critical insights for the development of disease-modifying therapies for this devastating disorder.
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