Generating patient-derived microglia to investigate neuroinflammation in MND

Alzheimer’s disease is anticipated to affect 100 million patients with an annual cost of US$1 trillion by 2050. Promising amyloid-clearing therapies have failed to translate to clinical outcomes, and new approaches targeting the underlying molecular pathways of Alzheimer’s disease are urgently required. There has been a ‘re-awakening’ to the critical role of microglia in Alzheimer’s disease pathology. However, our ability to translate abnormal microglial biology into clinically relevant advances has been greatly impaired by inadequate cell models. Microglia-like cells can now be routinely generated from human peripheral blood monocytes. The approach is cost-effective and rapid, and these induced microglia reveal a remarkably close relationship to mature human microglia in terms of cell surface marker expression, functional assays, and gene expression.

In this project, we will generate microglia-like cells from blood samples collected from Alzheimer’s patients, and people who are considered at high risk for Alzheimer’s disease. We will compare the cultured microglia to identify patient-specific immune abnormalities using a range of assays currently established in our lab. We will then screen individual patient microglia for the efficacy of immune-modulating compounds to identify effective patient-specific neurotherapeutics in ‘real-time’. This project will produce highly significant advances in patient-specific drug targeting for neuroinflammation in Alzheimer’s disease, leading to the development of real-time, individual therapeutic approaches with major clinical benefits, including identifying patient-specific drugs, selecting suitable patients for clinical trials, and monitoring drug efficacy during trials.