Recent insights into the role of glia and oxidative stress in Alzheimer's disease gained from Drosophila

Abstract

Here, we discuss findings made using Drosophila on Alzheimer's disease (AD) risk and progression. Recent studies have investigated the mechanisms underlying glia-mediated neuroprotection in AD. First, we discuss a novel mechanism of glial lipid droplet formation that occurs in response to elevated reactive oxygen species in neurons. The data suggest that disruptions to this process contribute to AD risk. We further discuss novel mechanistic insights into glia-mediated Aβ42-clearance made using the fly. Finally, we highlight work that provides evidence that the aberrant accumulation of reactive oxygen species in AD may not just be a consequence of disease but contribute to disease progression as well. Cumulatively, the discussed studies highlight recent, relevant discoveries in AD made using Drosophila.

Figure 1:. Elevation of ROS in neurons induces lipid droplet formation in glia.

(A) Diagram of a single ommatidium from the adult fly retina. Each ommatidium is composed of seven visible photoreceptor neurons surrounded by 2° and 3° pigment glia. The fly retina is composed of multiple, well organized ommatidia. (B) Diagram of lipid droplet (LD) formation in glia of the ommatidium when ROS is elevated in the neurons. (C) Representative images from studies showing glial LD formation in response to neuronal ROS in the fly retina. ROS was induced genetically by expressing an RNAi targeting the mitochondrial complex I subunit, NADH-ubiquinone oxidoreductase 42 (ND-42), in neurons [21]. Retinas from 1-2d animals were dissected and stained with a dye, BODIPY, which only fluoresces in the presence of neutral lipids. (D) Liu and colleagues investigated the pathway involved in glial LD formation during ROS and defined a number of key players [21,22]. Red indicates components that were directly investigated. Black indicates components of the pathway that need further study in this specific context while supportive data exists in other tissues/situations. Monocarbaxylates were shown indirectly to be involved as the loss of lactate dehydrogenases, which convert lactate to pyruvate for energy production, in both neurons and glia reduced LD formation. Loss of pyruvate dehydrogenases, which convert pyruvate to acetyl-CoA for entrance into the tricarboxylic acid (TCA) cycle, in neurons but not glia also disrupted glial LD formation.

Figure 2:. APOE status corresponds to ROS-induce glial lipid droplet formation and neurodegeneration.

Studies have shown that APOE is critical for glial LD formation when ROS is elevated in neurons using flies and mice [22,26]. The expression of the AD-protective allele, APOE2, in mutant flies that lacked the endogenous apolipoprotein, Glial Lazarillo (GLaz), demonstrated that this allele could continue to function in the pathway as LD formed at robust numbers and promoted neuron survival in conditions of elevated ROS (symbolized as blue, healthy neuron) [22]. In contrast, expression of the AD-risk allele, APOE4, in GLaz mutant flies shows almost a complete loss of LD formation, indicating that this allele was less functional in this pathway. The loss of glial LD formation was associated with increased neurodegeneration due to ROS (symbolized as red, unhealthy neuron). Overall, this highlights a novel mechanism underlying how APOE4 may confer risk in patients while connecting seemingly independent features of AD, lipid dysregulation and ROS.