HDLs and LDLs in the Brain: Characterizing the Lipid Secretome of Astrocytes

Abstract

Comprising up to a hundred‐fold more lipid than a typical cell, a neuron has extensive processes like dendrites and axons. The magnitude of the neuronal membrane surface area suggests the importance of the regulation of the lipids in the membrane to maintain normal neuronal function. While particles like high density lipoproteins (HDL), low density lipoproteins (LDL), and very low density lipoproteins (VLDL) normally circulate throughout the body for lipid regulation, these particles cannot pass the blood brain barrier. The brain must synthesize lipids locally in order to fulfill the biosynthetic/repair needs of the neurons. Lipid synthesis and transportation in the brain are facilitated by astrocytes, the helper glial cells of the nervous system. Astrocytes package and secrete lipids into “HDL/LDL‐like” particles, comprising a lipid core and a shell of proteins, like apolipoproteins, on the exterior. These particles function to regulate the lipid membrane of adjacent neurons, but they also vary in functionality depending on the particles' ratio of lipids to proteins (or how “LDL‐like” or “HDL‐like” the particles are). For example, apolipoprotein E (apoE) is a protein that is synthesized by astrocytes and is essential for cholesterol transportation to neurons. In Alzheimer's Disease (AD) specifically, the apoE4 polymorphism is implicated in higher AD frequency than other apoE polymorphisms because apoE4 is a weaker carrier of cholesterol than the other apoE variants. The apoE variant functionality suggests the imperative role of cholesterol homeostasis to maintain normal function in neurons. ApoE has also been shown to be the main constituent of the HDL‐like particles in the brain. Our initial studies of the lipid secretome of primary cultured mouse astrocytes revealed that the younger astrocytes secreted nearly ten‐fold less cholesterol than the older astrocytes while protein secretions between the different ages were not significantly different. These results suggest the “HDL‐like” particles are secreted more by the younger astrocytes while the “LDL‐like” particles are secreted by older astrocytes, revealing how aging plays a role in lipid homeostasis. We are continuing to isolate the lipid secretome of our primary astrocytes by using the lipid‐binding resin, Cleanascite. In order to understand the composition of these lipid particles, we are using thin layer chromatography to observe the presence of different lipids qualitatively and quantitatively.Support or Funding InformationMach Research Fellowship and Cowles Professorship