Microglia and Cholesterol Handling: Implications for Alzheimer's Disease

Abstract

Cholesterol is essential for brain function and structure, however altered cholesterol metabolism and transport are hallmarks of multiple neurodegenerative conditions, including Alzheimer's disease (AD). The well-established link between apolipoprotein E (APOE) genotype and increased AD risk highlights the importance of cholesterol and lipid transport in AD etiology. Whereas more is known about the regulation and dysregulation of cholesterol metabolism and transport in neurons and astrocytes, less is known about how microglia, the immune cells of the brain, handle cholesterol, and the subsequent implications for the ability of microglia to perform their essential functions. Evidence is emerging that a high-cholesterol environment, particularly in the context of defects in the ability to transport cholesterol (e.g., expression of the high-risk APOE4 isoform), can lead to chronic activation, increased inflammatory signaling, and reduced phagocytic capacity, which have been associated with AD pathology. In this narrative review we describe how cholesterol regulates microglia phenotype and function, and discuss what is known about the effects of statins on microglia, as well as highlighting areas of future research to advance knowledge that can lead to the development of novel therapies for the prevention and treatment of AD.

Keywords: Alzheimer’s disease; cholesterol; microglia.

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.