In our newly published narrative review in the special issue “Alzheimer’s disease- 115 Years After Its Discovery” in the journal Biomedicines we discuss the ins and outs of cholesterol handling in microglia, the immune cells of the brain, and discuss implications for Alzheimer’s disease.
In this review article we explore what is known about the effects of high and low cholesterol concentrations on microglia phenotype and function, and areas of research that still need to be explored to better understand this aspect of biology. Given the importance of microglia in driving the neuroinflammation that is associated with neurodegenerative diseases like Alzheimer’s disease, improving microglia function and decreasing microglia-associated inflammation are priority targets for finding new, effective treatments for Alzheimer’s disease. Understanding the role of cholesterol in this process may be a key for finding therapeutic solutions.
High density lipoproteins (HDL) are difficult to study: with a diameter range of 5-12nm they are too small to be studied by many tools that are routinely used to count, characterize and image other nanoparticles such as extracellular vesicles and cells, yet they are multi-molecular complexes that perform a wide array of functions which are dependent on their structure and composition. Despite more than 60 years of research, predominantly in the cardiovascular field due to the importance of HDL in clearing excess cholesterol arterial plaques, we understand very little about the complex biology of HDL particles and their myriad critical functions. We all know that not enough HDL is bad (low HDL-cholesterol is a part of the diagnostic criteria for metabolic syndrome), but recently it was found that too much HDL may also be bad (HDL-cholesterol concentrations >100 mg/dL are linked with higher mortality). What’s more, the amount of HDL in circulation (measured as HDL-cholesterol) only explains about 40% of the variability in the ability of HDL to perform their flagship function of cholesterol efflux, or removal of cholesterol from lipid-loaded macrophages. This means that measuring HDL as the amount of cholesterol carried in the particles is really only telling us a very small piece of the story. And it turns out that HDL composition – the proteins, lipids, lipid soluble components, and even RNA that they transport – HDL structure, and HDL particle size distribution, are all critical factors in how these particles do their jobs of protecting us from infection, blocked arteries, hyper inflammatory responses, and a number of additional functions. Yet we do not know how to improve HDL and truly even how to measure them. In the recently funded grant from the National Institutes of General Medical Sciences, the Zivkovic Lab will develop and optimize new technologies to study HDL particles and their complex biology so that we can harness this vast army of nanoparticles (over 6 quadrillion particles in every millimeter of plasma!) to improve and optimize health.