Glial Cells in Alzheimer’s Disease: Insights from Patient-Derived Models

The human brain is responsible for information processing and functions at various levels, ranging from movement to language and creativity. It consists of neurons and glial cells, including astrocytes and microglia. Alzheimer's disease is the most common form of dementia and is characterized by protein accumulations (amyloid and Tau) in the brain and changes in glial cells. Most patients suffer from the late-onset form of the disease, for which aging and the E4 variant of the APOE gene are the main risk factors. This thesis investigates the effect of APOE4 on astrocytes and microglia, using induced pluripotent stem cell (iPSC) models to mimic the brain in the lab. These iPSCs are derived from patients with Alzheimer’s Disease, making them highly suitable for studying disease processes. The iPSCs are differentiated into two types of models: (1) astrocytes isolated from other cells, and (2) brain organoids where astrocytes can interact with other brain cells. We found that APOE4 glia react differently than healthy APOE3 glia to two inflammatory stimuli, namely human serum and lipopolysaccharide. Additionally, significant differences were observed between the responses of APOE4 cells from patient A and patient B. This demonstrates that scientific research using iPSC models can reveal both general disease processes and patient-specific disease processes. The findings in this thesis provide insight into disrupted brain processes caused by APOE4. Understanding these mechanisms could lead to future treatments aimed at restoring disrupted functions and addressing the root causes of the disease.