Studying the role of environmental factors on microglia in Alzheimer's Disease using human brain organoids

Alzheimer's Disease (AD) is a chronic neurodegenerative disease characterised by abnormal protein accumulation in the form of beta-amyloid plaques and tau tangles. Most cases of AD are sporadic and have a multifactorial basis, manifesting from a mix of genetic predisposition and environmental factors. Genome wide association studies have mapped out the genetic basis of AD identifying common, but low risk changes in genes associated with the structure and function of the innate immune cells of the central nervous system, the microglia. Whereas environmental drivers of AD include age, infection, diet, and pollutant exposure. In AD, changes to the microglia and the development of plaques and tangles occur prior to symptom onset and possibly originate from the actions of environmental factors altering the cell biology of the brain. Thus, this project sets out to establish how environmental factors potentially prime or affect the differentiation of the microglia, altering the chance of an individual developing AD. To model these effects, we will use an in vitro human-derived 3D brain organoid model integrated with microglia exposed to differing environmental factors, creating a complex environment that mimics potential structural and functional differences that occur in the context of AD within the brain. Once this model has been established, we will use AD-derived human cell lines to further explore the relationship between genetic predisposition and the environment. Together this project will provide information on how the genetic-environment relationship alters an individual's chance of developing AD, potentially leading to new public health guidance and legislation.