Generation of Microglia-Containing APOE4 Cerebral Organoids as a Model of Down Syndrome-Associated Alzheimer’s Disease

Undergraduate Honors Thesis

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Citeable URL: https://scholar.colorado.edu/concern/undergraduate_honors_theses/f7623f24m

Abstract

Interactions between microglia, the innate immune cells of the central nervous system, and the cholesterol carrier apolipoprotein E may drive neurodegeneration in Down syndrome-associated Alzheimer’s disease and are promising potential therapeutic targets. However, much remains unknown about microglia in this context due to limitations of widely used animal and human monolayer cell culture models, necessitating the use of cerebral organoids as three-dimensional models of human brain tissue. Here, we hypothesized that cerebral organoids containing microglia could be generated from human induced pluripotent stem cells with trisomy 21 and the apolipoprotein E ε4 allele, the strongest genetic risk factor for Alzheimer’s disease, and that these models have the potential to fill existing knowledge gaps on cellular neuropathology. We cultured neural and hematopoietic progenitor cells to generate microglia-containing cerebral organoids as models of Down syndrome-associated Alzheimer’s disease. Immunohistochemistry revealed that hematopoietic progenitor cells failed to survive and mature into microglia in organoids, and that other methods should be tried for generating microglia-containing cerebral organoids with trisomy 21 and apolipoprotein E ε4 in the future. We hope that our findings will contribute to the eventual successful generation of these models for the advancement of medical care for people with Down syndrome-associated Alzheimer’s disease.

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