Regulation of ApoE in microglia

• Applicant: Privatdozentin Dr. Susanne Krasemann, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445704749

Alzheimer’s disease (AD) is the most common form of dementia with 35 million people affected worldwide. Currently, no treatment options are available. While research was neuron centered for decades, microglia, the innate immune cells of the brain, were implicated in AD pathogenesis due to genome-wide association studies. Recent data even suggest that microglia are not just participants, but active drivers of disease. Therefore, microglia emerge as a promising therapeutic target in AD. We identified a disease associated microglia expression signature that is characterized by significant upregulation of ApoE in mouse models and human AD. We could show that ApoE is orchestrating a specific downstream program in microglia. Our preliminary experiments suggest that the transcription factor Egr1 could negatively influence ApoE expression. Thus, we hypothesize that Egr1 is a potent repressor of ApoE.In this proposal, we want to investigate the capability of the transcription factor Egr1, to repress ApoE dysregulation in microglia in disease and thereby restore necessary microglia functions. For this, we will first identify the Egr1 binding site within the ApoE-promotor region. Moreover, we will determine other targets of Egr1 in microglia beside ApoE in a microglia cell culture model. Next, we want to investigate, if Egr1 is capable of normalizing ApoE expression and restore a functional signature in dysregulated microglia in AD in vivo. To this end, we plan to use a novel AD mouse model for the specific spatio-temporal expression of Egr1, where Egr1 is specifically expressed in microglia. We expect a significant improvement in treated mice regarding pathology and behavior. Mice will be thoroughly characterized for behavioral improvement, potential reduction of Abeta plaque burden and microglia expression signature and phenotype. Many drugs work beautifully in AD mouse model, but so far, they have all failed in clinical trials with human AD patients. Therefore, we plan to use our newly established model to generate microglia like cells from human blood-derived monocytes, to investigate the effect of Egr1 on their expression signature. In addition, we will perform functional assays in this human model system.With our research strategy, we expect to address basic questions about the regulation of ApoE in diseased microglia, but also investigate the therapeutic potential to restore microglia functionality in AD.

• DFG Programme: Research Grants