Studying the Role of Microglial LXR in Control of AD Risk Genes

The goal of this project is to generate and functionally characterize hiPSC-derived microglia lacking transcription factors involved in lipid-clearance machinery in disease-relevant context. I aim to understand how transcription factors that regulate lipid clearance machinery control microglial functions in AD brains. To this end, I will generate human microglia (iMGL) derived from induced pluripotent stem cells that lack LXRa and LXRb as well as iMGL that lack repressors of LXRa/b to address potential gain of LXR function in disease-relevant context. I will further characterize function of modified iMGL in vitro and in specialized mouse models looking at microglial recruitment to plaques, phagocytosis, lipid clearance processes and impact on neurodegeneration.

Alzheimer’s disease (AD) is a chronic, incurable neurodegenerative disease characterized by deposition of ß-amyloid plaques, neurofibrillary tangles, chronic activation of immune cells in the brain and abnormal accumulation of lipids. Analysis of genetic factors contributing to AD point to the critical role of brain immune cells (microglia) and functions that they exert such as efficient removal of dying cells in the process called phagocytosis. In AD brains immune cells are unable to properly remove amyloid plaques and they sustain inflammation contributing to disease progression. This project will test whether LXRs and BHLHE40/41 are master regulators of microglial phagocytosis using human cells carrying AD mutations. With this information we will be able to propose novel therapeutic targets for AD.

Unique aspect of this proposal is to address cell-autonomous role of LXRa and LXRb in human microglia that has not been investigated yet. This work will also help to elucidate the role of lipid clearance machinery and its impact on disease-associated microglia in AD models. Finally, generated human induced pluripotent stem cells (hiPSC) lacking LXRa/b or their repressor will be valuable tool to study role of these transcription factors in other cell types by differentiation neurons, astrocytes and oligodendrocytes.

Completing this project will shed a new light on microglial role of LXRs in control of lipid clearance and immune response in normal and diseased AD brains. This work may open new avenues for therapeutic intervention for AD. Additionally, this work may also uncover which transcription factor controls transition from homeostatic to disease-associated microglia – a population of microglia frequently found in neurodegeneration – what will further help to prioritize small molecules targeting this population.