The current therapeutic strategies for treatment of Alzheimer’s disease have yet to make an impact on the disease course in people with the disorder. New approaches to treatment are urgently needed and one of the major areas of research is the development of compounds to control the inflammatory changes in the brain during the disease. This abnormal immune response in the Alzheimer’s patient brain is driven largely by altered behaviour of microglia, the resident immune cell of the brain. However, lack of access to patient microglia has greatly impeded research in this field. Although microglia can now be generated from patient induced-pluripotent stem cells, this approach is time-consuming and costly and is largely restricted to detailed studies on cells with rare familial mutations.
A new approach has been developed that allows the generation of microglia-like cells from human blood-derived monocytes. This is a rapid process producing cells within 14 days that express a highly ramified microglia morphology, together with strong expression of microglia-specific markers. Consequently, these cells offer an important insight into microglial function in Alzheimer’s patients that cannot be gained through any alternative approach. Due to the ease of generation, this approach is highly suited to examination of patient and healthy control microglia on a larger scale, and can provide real-time information on patient microglia responses to potential drug compounds.
In this project, we will collect blood samples from people with Alzheimer’s disease, as well as those at risk, and healthy controls. From the blood samples, we will isolate monocytes and culture these cells for up to three weeks in medium containing specific cytokines. This will allow us to generate mature cultures of patient and control microglia-like cells.
We will compare the inflammatory response of the patient and control cells in a range of tests to help understand how each patient’s microglia respond to different inflammatory stimuli. We will also assess how the patient microglia respond to different compounds aimed to modulate the inflammatory response to determine if some patients respond differently to certain compounds. This will allow us to develop a proof-of-concept that patient-derived microglia can be used in a personalized screen for potential therapeutic compounds to regulate neuroinflammation. Finally, we will perform an RNA analysis on collected patient microglia to determine the gene expression profile of each. This will provide us with a readout that in future can be used to determine if a patient should respond to a particular immune-modulatory compound based on the gene profile of their microglia.
This project has the potential to revolutionize the approach to personalized inflammatory modulation for people with Alzheimer’s disease. It will allow us for the first time to measure an individual patient’s microglial response and potential therapeutic action of inflammatory modulators within a short time frame (weeks). This proof of concept can subsequently be expanded for screening of larger libraries of potential inflammatory modulation compounds currently in clinical use to provide individualized patient treatment options. Techniques will include microglia and neural stem cell culture, molecular studies (i.e. RT-PCR), microscopy (confocal imaging), various biochemical assays (i.e. cytokine bead arrays) and protein analysis (western blot).
PhD project but may also be considered for an Honours project.