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

Abstract

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.

Intense physical exercise potentiates glucose inhibitory effect over food intake of male Wistar rats

“…New evidence shows that support cells in the central nervous system are important to regulate feeding (Elizondo‐Vega et al., , ; Liu, MacKenzie, Putluri, Maletić‐Savatić, & Bellen, ; Yang et al., ). The astrocyte–neuron lactate shuttle hypothesis suggests that astrocytes can regulate feeding by providing neurons with lactate, via the MCTs (Pérez‐Escuredo et al., ).…”

Glial α‐synuclein promotes neurodegeneration characterized by a distinct transcriptional program in vivo

“…Similar to mammalian glia, Drosophila glia include multiple specialized cell types (Kremer, Jung, Batelli, Rubin, & Gaul, ) and are essential for neuronal development (Booth, Kinrade, & Hidalgo, ; Sepp, Schulte, & Auld, ) and maintenance (Xiong & Montell, ). In the adult nervous system, they serve many of the same specialized functions as mammalian glia, including phagocytic clearance of cellular debris (Doherty, Logan, Taşdemir, & Freeman, ; MacDonald et al, ), participation in innate immunity (Kounatidis & Chtarbanova, ), blood–brain barrier formation (DeSalvo et al, ), glutamate recycling (Farca Luna, Perier, & Seugnet, ; Rival et al, ), protection of axons in white matter (Logan et al, ), and protection of neurons from reactive oxygen species through lipid droplet formation (L. Liu, MacKenzie, Putluri, Maletić‐Savatić, & Bellen, ; L. Liu et al, ).…”

Neuronal lactate levels depend on glia‐derived lactate during high brain activity in Drosophila

“…It was shown that Drosophila glial cells in vitro release alanine and lactate when fueled by trehalose or glucose and that knockdown of glycolytic genes in glia, but not in neurons, leads to severe neurodegeneration (Volkenhoff et al, ). Moreover, it was suggested that Drosophila glial cells provide lactate to neurons, which use it as a substrate to form fatty acids that in turn are transported back to glial cells to be stored as lipid droplets (Liu, MacKenzie, Putluri, Maletic‐Savatic, & Bellen, ). Despite the increasing evidence of the role of lactate, there is little knowledge about the characteristics of the movement of lactate between glial cells and neurons, particularly during activity.…”