Regulation of ApoE in microglia
Final Report Abstract
After decades of a neuro-centric few on Alzheimer’s disease (AD), the most common form of dementia worldwide, it is now well accepted that neuro-inflammation plays a substantial role in disease processes. Especially microglia cells, the innate immune cells of the brain, were implicated in AD pathogenesis due to genome-wide association studies. Microglia get dysregulated and display an altered expression and functional profile that is especially apparent in the vicinity of amyloid-β-plaques. We and others identified a disease associated microglia expression signature that is characterized by significant upregulation of ApoE in mouse models and human AD. However, it is still not fully understood, if these changes in expression are beneficial or if more pro-inflammatory detrimental functions stand out. ApoE is one of the most dysregulated microglial genes in disease. The aim of this project was to characterize in more detail the role of the transcription factor EGR1 in the dysregulation of microglia, since our preliminary data suggested a reciprocal regulation of ApoE and EGR1. In our project, we could identify and characterize a putative binding site in the Apoe promotor. Carriers of the ApoE4 allele have a significantly increased risk to develop sporadic AD. It became also clear that the detrimental role of ApoE4 was not only limited to its interaction with amyloid-β, but also played a role in microglia dysregulation. We could show that carriers of ApoE4 displayed higher expression of EGR1 in disease than those with ApoE3. In a mouse model for Tauopathy, this was accompanied with a more non-reactive microglia state. To study the role of EGR1 in microglia in disease in more detail, our aim was to generate a mouse model for the spatio-temporal expression of EGR1. Unfortunately, the first version of the targeting construct was unstable and did not result in a functional mouse model. After intensive reconstruction, we were successful in generating a mouse that is currently back-crossed with the relevant inducer lines and disease models. Using a model to generate microglia like cells (MDMi) from human blood-derived monocytes, we could show that ApoE genotypes are well represented in the cohort, with a trend to higher ApoE2 and lower ApoE4 frequencies. However, these primary cells are too sensible for transfection and we thus limited our studies to treatments with AD-related cues to study expression dysregulation. As expected for primary cells, the variability was very high between donors and analyses are still ongoing. In summary, we could show the influence of EGR1 on ApoE expression in different systems, however, further experiments are necessary to clarify the whole picture of the role of EGR1 in microglia dysregulation.
Publications
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Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia. Acta Neuropathologica, 144(3), 589-601.
Sepulveda-Falla, Diego; Sanchez, Justin S.; Almeida, Maria Camila; Boassa, Daniela; Acosta-Uribe, Juliana; Vila-Castelar, Clara; Ramirez-Gomez, Liliana; Baena, Ana; Aguillon, David; Villalba-Moreno, Nelson David; Littau, Jessica Lisa; Villegas, Andres; Beach, Thomas G.; White, Charles L.; Ellisman, Mark; Krasemann, Susanne; Glatzel, Markus; Johnson, Keith A.; Sperling, Reisa A. ... & Quiroz, Yakeel T.
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APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints. Nature Immunology, 24(11), 1839-1853.
Yin, Zhuoran; Rosenzweig, Neta; Kleemann, Kilian L.; Zhang, Xiaoming; Brandão, Wesley; Margeta, Milica A.; Schroeder, Caitlin; Sivanathan, Kisha N.; Silveira, Sebastian; Gauthier, Christian; Mallah, Dania; Pitts, Kristen M.; Durao, Ana; Herron, Shawn; Shorey, Hannah; Cheng, Yiran; Barry, Jen-Li; Krishnan, Rajesh K.; Wakelin, Sam ... & Butovsky, Oleg
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APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease. New England Journal of Medicine, 391(17), 1660-1661.
Quiroz Y.T., Aguillon D., Aguirre-Acevedo D.C., Vasquez D., Zuluaga Y., Baena A.Y., Madrigal L., Hincapié L., Sanchez J.S., Langella S., Posada-Duque R., Littau J.L., Villalba-Moreno N.D., VilaCastelar C., Ramirez Gomez L., Garcia G., Kaplan E., Rassi Vargas S., Ossa J.A. ... & Arboleda-Velasquez J.F.
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APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer’s cases. Frontiers in Molecular Neuroscience, 17.
Perez-Corredor, Paula; Vanderleest, Timothy E.; Vacano, Guido N.; Sanchez, Justin S.; Villalba-Moreno, Nelson D.; Marino, Claudia; Krasemann, Susanne; Mendivil-Perez, Miguel A.; Aguillón, David; Jiménez-Del-Río, Marlene; Baena, Ana; Sepulveda-Falla, Diego; Lopera, Francisco; Quiroz, Yakeel T.; Arboleda-Velasquez, Joseph F. & Mazzarino, Randall C.
