Scientists from the Baylor College of Medicine say that a cellular mechanism that disrupts the interaction between neurons and glia can result in neurodegeneration. Their study (“The Glia-Neuron Lactate Shuttle and Elevated ROS Promote Lipid Synthesis in Neurons and Lipid Droplet Accumulation in Glia via APOE/D”), which appears in Cell Metabolism, may shed light on the development of diseases as Alzheimer's, they add.
“Elevated reactive oxygen species (ROS) induce the formation of lipids in neurons that are transferred to glia, where they form lipid droplets (LDs). We show that glial and neuronal monocarboxylate transporters (MCTs), fatty acid transport proteins (FATPs), and apolipoproteins are critical for glial LD formation. MCTs enable glia to secrete and neurons to absorb lactate, which is converted to pyruvate and acetyl-CoA in neurons,” write the investigators.
“Lactate metabolites provide a substrate for synthesis of fatty acids, which are processed and transferred to glia by FATP and apolipoproteins. In the presence of high ROS, inhibiting lactate transfer or lowering FATP or apolipoprotein levels decreases glial LD accumulation in flies and in primary mouse glial-neuronal cultures. We show that human APOE can substitute for a fly glial apolipoprotein and that APOE4, an Alzheimer’s disease susceptibility allele, is impaired in lipid transport and promotes neurodegeneration, providing insights into disease mechanisms.”
“Using fruit flies, we are able to thoroughly study the functions of proteins that are shared between flies and humans. Often, perturbation of these proteins leads to neurodegenerative characteristics in flies and neurodegenerative diseases in people. By studying how these genes cause defects in fly and mouse models, we can improve our insights into the mechanisms related to human disease,” said Hugo J. Bellen, DVM, Ph.D., professor of neuroscience and molecular and human genetics at Baylor College of Medicine and an investigator at the Howard Hughes Medical Institute.
According to Dr. Bellen, two years ago, Lucy Liu, Ph.D., a member of his lab, found that genes involved in neurodegeneration help cause damage to neurons and glia by inducing high levels of free radicals (oxidative stress) and accumulation of lipid droplets in glial cells.
“Using electron microscopy, we observed lipid droplet accumulation in glia before obvious symptoms of neurodegeneration,” Dr. Liu said. “In the presence of high levels of oxidative stress, neurons produce an overabundance of lipids. The combination of free radicals and lipids, which produces peroxidated lipids, is detrimental to cellular health. Neurons try to avoid this damage by secreting these lipids, and apolipoproteins carry them to glia cells. Glia store the lipids in lipid droplets, sequestering them from the environment and providing a protective mechanism.”
Dr. Liu and her colleagues discovered that the storage of lipid droplets in glia protects neurons from damage as long as the free radicals do not destroy the lipid droplets. When the lipid droplets are destroyed, cell damage and neurodegeneration occur.
“Our research brought us to a fascinating and unexpected finding,” continued Dr. Liu. “Approximately 15% of the human population carries apolipoprotein APOE4. Since APOE4 was first linked to Alzheimer's disease almost 30 years ago, it remains the strongest known genetic risk factor for this disease. Meanwhile, APOE2, which is slightly different from APOE4, is protective against the disease. This evidence suggests that APOE is important for proper brain function, but we know little about how APOE itself may lead to Alzheimer's disease.”
Apolipoproteins APOE2, APOE3, and APOE4 have different abilities to transfer lipids from neurons to glia and hence differ in their ability to mediate the accumulation of lipid droplets, according to the scientists.
“APOE2 and APOE3 can effectively transfer lipids into glia,” said Dr. Liu. “On the other hand, APOE4 is practically unable to carry out this process. This results in a lack of lipid droplet accumulation in glia and breakdown of the protective mechanism that sequesters peroxidated lipids. This fundamental difference in the function in APOE4 likely primes an individual to be more susceptible to the damaging effects of oxidative stress, which becomes elevated with age.”
“Another contribution of this study is that glia play an important protective role against oxidative stress in neurodegeneration,” added a Dr. Bellen. “Mutations that lead to a breakdown of this support system between neurons and glia can pave the way to neurodegeneration, and it seems that free radicals are at the root of a key aspect of this process.”