Neuronal ROS-induced glial lipid droplet formation is altered by loss of Alzheimer’s disease–associated genes

M. Moulton, Scott Barish, Isha Ralhan, Jinlan Chang, Lindsey D. Goodman, Jake G. Harland, Paul C. Marcogliese, J. Johansson, Maria S. Ioannou, H. Bellen
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引用次数: 46

Abstract

Significance Multiple studies have implicated dozens of risk loci that may be associated with Alzheimer’s disease (AD), but common mechanisms underlying how they may contribute to disease onset or progression remain elusive. This study identifies cell-specific roles for Drosophila orthologs of AD risk genes in lipid droplet formation that, when disrupted, lead to neurodegeneration. Our work reinforces a critical role for the sequestration of peroxidated lipids in glia, and places Apolipoprotein E ε4 (APOE4) with other AD risk factors in the transfer process of lipids from neurons to glia to form lipid droplets. A growing list of Alzheimer’s disease (AD) genetic risk factors is being identified, but the contribution of each variant to disease mechanism remains largely unknown. We have previously shown that elevated levels of reactive oxygen species (ROS) induces lipid synthesis in neurons leading to the sequestration of peroxidated lipids in glial lipid droplets (LD), delaying neurotoxicity. This neuron-to-glia lipid transport is APOD/E-dependent. To identify proteins that modulate these neuroprotective effects, we tested the role of AD risk genes in ROS-induced LD formation and demonstrate that several genes impact neuroprotective LD formation, including homologs of human ABCA1, ABCA7, VLDLR, VPS26, VPS35, AP2A, PICALM, and CD2AP. Our data also show that ROS enhances Aβ42 phenotypes in flies and mice. Finally, a peptide agonist of ABCA1 restores glial LD formation in a humanized APOE4 fly model, highlighting a potentially therapeutic avenue to prevent ROS-induced neurotoxicity. This study places many AD genetic risk factors in a ROS-induced neuron-to-glia lipid transfer pathway with a critical role in protecting against neurotoxicity.
神经元ros诱导的胶质脂滴形成被阿尔茨海默病相关基因的缺失所改变
多项研究已经发现了数十个可能与阿尔茨海默病(AD)相关的风险位点,但它们如何导致疾病发生或进展的共同机制尚不清楚。本研究确定了AD风险基因的果蝇同源基因在脂滴形成中的细胞特异性作用,当脂滴被破坏时,导致神经退行性变。我们的研究强调了过氧化脂质在胶质细胞中隔离的关键作用,并将载脂蛋白E ε4 (APOE4)与其他AD危险因子一起置于脂质从神经元到胶质细胞形成脂滴的转移过程中。越来越多的阿尔茨海默病(AD)遗传风险因素正在被确定,但每种变异对疾病机制的贡献在很大程度上仍然未知。我们之前的研究表明,活性氧(ROS)水平升高会诱导神经元中的脂质合成,导致胶质脂滴(LD)中过氧化脂质的隔离,从而延缓神经毒性。这种神经元到胶质的脂质转运依赖于APOD/ e。为了确定调节这些神经保护作用的蛋白,我们测试了AD风险基因在ros诱导的LD形成中的作用,并证明了几种基因影响神经保护性LD的形成,包括人类ABCA1、ABCA7、VLDLR、VPS26、VPS35、AP2A、PICALM和CD2AP的同源基因。我们的数据还表明,ROS增强了果蝇和小鼠的a - β42表型。最后,ABCA1的肽激动剂在人源化APOE4果蝇模型中恢复胶质LD的形成,强调了防止ros诱导的神经毒性的潜在治疗途径。这项研究发现,在ros诱导的神经元到胶质细胞脂质转移途径中,许多AD遗传危险因素在保护神经毒性方面起着关键作用。
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