Editors' ChoiceAlzheimer’s Disease

Where, oh where has my lipid drop gone?

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Science Translational Medicine  18 Oct 2017:
Vol. 9, Issue 412, eaap8170
DOI: 10.1126/scitranslmed.aap8170

Abstract

Stress-mediated lipid droplet formation requires neuronal lactate and is impaired by APOE4.

The brain has a voracious appetite for energy and is arguably the most metabolically demanding of all organs. However, despite the importance of energy metabolism in the brain, key details regarding the processing and transport of metabolic substrates between brain cells remain obscure. This study investigates the metabolic origin of lipid droplets, organelles within glial cells that store lipids and may be key players in the brain’s compensatory response to oxidative stress.

Here, Liu et al. sought to explore the role of molecules involved in energy production and lipid transport on the formation of lipid droplets. Leveraging Drosophila, cellular, and rodent models, they identified candidate genes conserved across species and expressed in the brain that could impact lipid production and transport. Through elegant experiments modifying expression and activity of these genes in glia and neurons, the group found that formation of glial lipid droplets requires monocarboxylate transport proteins–mediated lactate transfer from glia to neurons. Lactate accumulation in neurons triggers production of lipids that are subsequently transported to glial cells where they form lipid droplets. Interestingly, the authors found that apolipoprotein E (APOE) plays an important role in the transfer of lipids between neurons and glia. When human APOE variants (APOE2-4) were used to replace the APOE functional analog glaz in Drosophila models, it was shown that APOE2 and APOE3 [associated with decreased and neutral risk of Alzheimer’s Disease (AD) in humans] could rescue the decrease in lipid droplet formation that resulted from loss of glaz. On the contrary, APOE4, known to be associated with increased risk of developing AD, poorly rescued the loss of glaz and was associated with very low formation of lipid droplets even under conditions of overexpression and oxidative stress. Over time, the APOE4 variant was also associated with increased cell loss. These findings suggest that APOE-mediated lipid transport affects the cell’s ability to respond to stress conditions and ultimately could compromise cellular health.

Overall, by exploring the tightly integrated relationship of neuron and glia metabolism, investigators showed that glial lactate is used for lipid synthesis within neurons. Mitochondrial dysfunction and oxidative stress result in increased neuronal lipid production and transport of lipids from neurons to glia for storage in lipid droplets. APOE appears to be key in this transport, with the AD risk factor variant APOE4 less effective than other alleles at transferring lipids. While additional work in mice and humans is needed to fully elucidate the relationship between lactate metabolism, lipid droplets, and APOE4, these findings provide an important path toward the understanding how oxidative stress can impact fuel metabolism and brain health.

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