Alzheimer’s disease (AD) is a leading cause of dementia, with no current treatments to stop brain damage after onset. A rare genetic mutation called APOE3 Christchurch was found in a woman genetically predisposed to develop dementia in her 40s, but who remained healthy until her 70s. Understanding how the APOE3 mutation protects the brain could lead to new treatments for many patients, even those without the protective mutation. We made a mouse model of the APOE3 mutation and bred it with mice that have tau pathology, which is present in patients with AD. We found that microglia, the brain’s immune cells, and astrocytes, other neuron-supporting cells, behave differently when the protective APOE3 mutation is present. Microglia reduce harmful immune signals and clear toxic tau more efficiently, while astrocytes boost their energy and antioxidant production. We focused on a specific pathway that decreased in the mouse microglia with the protective APOE3 mutation, and we utilized a drug to inhibit this pathway. The drug was able to recapitulate the protection observed in mice that had the APOE3 mutation, making this pathway relevant for future studies in patients who do not exhibit the APOE3 protective mutation. The remaining part of this projectwill focus on astrocytes, the other neuron-supporting cell type, and how astrocyte interactions with neurons can be protective. We will study the health of astrocyte mitochondria, which are important for energy production, as well as astrocyte lipid profiles, since the APOE3 protein is a lipid transporter.
