The Glia-Neuron Lactate Shuttle and Elevated ROS Promote Lipid Synthesis in Neurons and Lipid Droplet Accumulation in Glia via APOE/D

Abstract

<p class="first" id="P1">Elevated reactive oxygen species (ROS) induce the formation of lipids in neurons that are transferred to glia where they form lipid droplets (LD). We show that glial and neuronal monocarboxylate transporters (MCTs), fatty acid transport proteins (FATP), 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. 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 all decrease 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. </p><p id="P2">Liu et al. unravel an evolutionarily conserved mechanism which brings neuron-glia metabolic cooperation full circle. They show that glial lactate can fuel neuronal lipogenesis in response to ROS; in turn, neuronal lipids are transported and stored in glia as lipid droplets. The inability to transport lipids to glia for lipid droplet formation leads to accelerated neurodegeneration under stress. </p><p id="P3"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/8d59dfe5-14ed-4729-821a-b401ab4d336a/PubMedCentral/image/nihms904216u1.jpg"/> </div> </p>