Figure 1.

High cholesterol concentrations and disease-associated microglia (DAM). When cholesterol concentrations are low or normal the amount of amyloid-β (Aβ) production is low, coupled with normal microglia Aβ clearance, and a homeostatic microglia phenotype with normal levels of cholesterol efflux, normal production of inflammatory signals and reactive oxygen species (ROS). Conversely, exposure to high cholesterol concentrations leads to increased production of Aβ by neurons due to colocalization of amyloid precursor protein (APP) and gamma secretase in the plasma membrane. Concurrently, high cholesterol concentrations lead to induction of the DAM phenotype, in which increased inflammatory signaling, increased production of ROS, and decreased cholesterol efflux hinder the ability of microglia to clear Aβ, further increasing the concentration of Aβ oligomers and driving plaque formation. Created with BioRender.com.