Haynes PR, Pyfrom ES, Li Y, Stein C, Cuddapah VA, Jacobs JA, Yue Z, Sehgal A.
A neuron-glia lipid metabolic cycle couples daily sleep to mitochondrial homeostasis.
Nat Neurosci. 2024 Feb 15;
PubMed.
This is a fantastic study. It addresses fundamental issues of brain bioenergetic metabolism that relate and link to several AD-relevant phenomena, including neuron-glia interplay, apolipoprotein E biology, lipid metabolism, oxidative stress, circadian rhythms, sleep, and mitochondrial biology. While “mitochondriacs” will find the overall findings unsurprising, it is nevertheless quite exciting to see the connections between mitochondria and sleep laid out at this level of detail. It is thrilling to think about how this system arose through evolution and how it ties to AD.
In general, we continuously run our neuron mitochondria when awake, which initiates the need for regular mitochondrial and probably general cell tune-ups. To accomplish this, worn-out, likely oxidized neuron membrane material is shipped to astrocytes through an ApoE-dependent transfer event, and the transferred membrane is first stored and then catabolized through fatty acid beta oxidation in astrocyte mitochondria.
To better understand the need for this neuron-astrocyte interaction, one needs to know that neuron mitochondria are not wired to perform fatty acid oxidation. The astrocyte mitochondria fatty acid catabolism event happens during sleep, and neuron mitochondria also take advantage of the sleep-related downtime to repair themselves. By the time awakening occurs, the neuron mitochondria are ready to go another round, and the bioenergetic metabolism-oxidized fatty acid byproducts have been eliminated and likely even recycled. For all this to happen, of course, we simply need to sleep.
The authors speculate that when sleep breaks down, this biological system cannot perform, and a resultant disruption of the cycle may promote neurodysfunction and neurodegeneration. This could turn out to be the case, but the nature of the modeling arguably limits our ability to extrapolate to the human AD state.
From the perspective of the mitochondrial cascade hypothesis, one might speculate that failing mitochondria would throw this whole system out of whack, with ApoE isoform status helping to determine the extent of the resulting disequilibrium. In other words, sleep disruption may prove to be less of a driver of AD, and more a consequence of AD mitochondrial strain.
This exciting new paper from the Seghal lab makes an unexpected connection between reactive oxygen species (ROS), lipid metabolism, and sleep. Previous work had shown that neurons release ROS-damaged peroxidated lipids when overexcited or stressed; these lipids are then taken up by glia and temporarily stored in lipid droplets before being metabolized in mitochondria (Liu et al., 2015; Ioannou et al., 2019). Most previous work on this process focused on disease conditions. However, Haynes and colleagues discovered that glial lipid droplet accumulation occurs as part of a daily rhythm: in flies, glia accumulate lipid droplets during the day in response to normal neuronal activity, which are then metabolized by glial mitochondria at night during sleep. The daily transfer of lipids from neurons to glia required neuronal lazarillo (NLaz), a fly apolipoprotein similar to human apolipoprotein E (APOE): knocking down NLaz reduced glial lipid droplet accumulation.
Interestingly, reducing the expression of glial lazarillo (GLaz) resulted in more lipid droplets rather than fewer, which was unexpected. The authors suggest that GLaz may play a function in lipid droplet formation or metabolism within glia, in addition to its role in transporting lipids between cells. This is consistent with recent results from my lab showing that APOE can localize directly to the surface of glial lipid droplets, with APOE knockdown causing larger lipid droplets (Windham et al., 2024). Importantly, reducing either NLaz or GLaz expression resulted in sleep disruption.
This work identifies neuron-glia lipid transport and metabolism as an important new regulator of sleep and raises fascinating questions about how these findings might translate to humans, especially in the context of Alzheimer’s disease. The E4 variant of APOE is the biggest genetic risk factor for developing late-onset Alzheimer’s disease. APOE4 mice were previously found to be more sensitive to sleep disruption than APOE3 mice, with sleep disruption in E4 mice resulting in increased Aβ deposition and tau seeding (Wang et al., 2023). Sleep disturbances are also associated with Alzheimer’s and other neurodegenerative diseases.
This work opens new avenues to explore the mechanistic relationship between APOE, sleep, and AD. Questions remain about how exactly glial lipid metabolism regulates sleep need, or sleep behavior. In addition, it remains to be seen whether human APOE is important for intercellular lipid transfer and/or glial lipid droplet metabolism in the context of sleep, and whether any of these functions are affected by APOE genotype.
References:
Liu L, Zhang K, Sandoval H, Yamamoto S, Jaiswal M, Sanz E, Li Z, Hui J, Graham BH, Quintana A, Bellen HJ.
Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration.
Cell. 2015 Jan 15;160(1-2):177-90.
PubMed.
Ioannou MS, Jackson J, Sheu SH, Chang CL, Weigel AV, Liu H, Pasolli HA, Xu CS, Pang S, Matthies D, Hess HF, Lippincott-Schwartz J, Liu Z.
Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity.
Cell. 2019 May 30;177(6):1522-1535.e14. Epub 2019 May 23
PubMed.
Windham IA, Powers AE, Ragusa JV, Wallace ED, Zanellati MC, Williams VH, Wagner CH, White KK, Cohen S.
APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size.
J Cell Biol. 2024 Apr 1;223(4) Epub 2024 Feb 9
PubMed.
Wang C, Nambiar A, Strickland MR, Lee C, Parhizkar S, Moore AC, Musiek ES, Ulrich JD, Holtzman DM.
APOE-ε4 synergizes with sleep disruption to accelerate Aβ deposition and Aβ-associated tau seeding and spreading.
J Clin Invest. 2023 Jul 17;133(14)
PubMed.
This is an exciting finding. It builds on work from Hugo Bellen’s lab, which showed that astrocytes can take up lipid droplets from stressed/injured neurons as a neuroprotective mechanism. This new paper provides a novel connection to sleep deprivation, which is bi-directional. This is really interesting.
Our lab recently published data showing that the circadian clock protein REV-ERBalpha can regulate microglial lipid droplets, so both sleep and circadian rhythms may influence lipid droplets in the brain. One implication of this paper is that a possible novel function of sleep (or circadian rhythms) might be to limit activity-induced lipid peroxidation and mitochondrial dysfunction.
This work helps us understand how sleep restriction/disruption can influence brain health and perhaps neurodegenerative pathology, though this was not specifically tested here. We know that people with AD have sleep disruptions, and this study gives us a new idea of why that might happen.
There are a couple of caveats to consider, however. Lipid droplets seem to be very prominent in flies and are seen in a variety of pathological conditions, as well as in cell culture, but they are less common in mouse brain and more difficult to induce in vivo. Moreover, this paper does not examine this phenomenon in any AD models, so the relevance to AD is speculative. However, it is an exciting finding and will certainly spur more research on this topic in mammalian systems and AD models.
This is a beautiful study with compelling results. That the authors discovered a role for glia in protecting neurons from wake-related oxidative stress is quite unexpected and eye-opening.
The next step will be to test the extent to which this mechanism applies to mammalian sleep. Mice and humans spend 15-20 percent of their total sleep in REM sleep, during which neuronal activity is even higher than in waking. Further, REM sleep accounts for most of the sleep during development. Thus, it will be very interesting to see whether this newly discovered shuttle system is restricted to NREM sleep in mammals.
Also, neurons in several brain regions, including the hippocampus, are equally active in waking as in sleep, and often more active in sleep (for instance, many cells in the dentate gyrus). Thus the “stress” of waking, and therefore the need to sleep, is likely to depend not only on neuronal activity, but also on other factors.
Comments
University of Kansas
This is a fantastic study. It addresses fundamental issues of brain bioenergetic metabolism that relate and link to several AD-relevant phenomena, including neuron-glia interplay, apolipoprotein E biology, lipid metabolism, oxidative stress, circadian rhythms, sleep, and mitochondrial biology. While “mitochondriacs” will find the overall findings unsurprising, it is nevertheless quite exciting to see the connections between mitochondria and sleep laid out at this level of detail. It is thrilling to think about how this system arose through evolution and how it ties to AD.
In general, we continuously run our neuron mitochondria when awake, which initiates the need for regular mitochondrial and probably general cell tune-ups. To accomplish this, worn-out, likely oxidized neuron membrane material is shipped to astrocytes through an ApoE-dependent transfer event, and the transferred membrane is first stored and then catabolized through fatty acid beta oxidation in astrocyte mitochondria.
To better understand the need for this neuron-astrocyte interaction, one needs to know that neuron mitochondria are not wired to perform fatty acid oxidation. The astrocyte mitochondria fatty acid catabolism event happens during sleep, and neuron mitochondria also take advantage of the sleep-related downtime to repair themselves. By the time awakening occurs, the neuron mitochondria are ready to go another round, and the bioenergetic metabolism-oxidized fatty acid byproducts have been eliminated and likely even recycled. For all this to happen, of course, we simply need to sleep.
The authors speculate that when sleep breaks down, this biological system cannot perform, and a resultant disruption of the cycle may promote neurodysfunction and neurodegeneration. This could turn out to be the case, but the nature of the modeling arguably limits our ability to extrapolate to the human AD state.
From the perspective of the mitochondrial cascade hypothesis, one might speculate that failing mitochondria would throw this whole system out of whack, with ApoE isoform status helping to determine the extent of the resulting disequilibrium. In other words, sleep disruption may prove to be less of a driver of AD, and more a consequence of AD mitochondrial strain.
View all comments by Russell SwerdlowUniversity of North Carolina at Chapel Hill
This exciting new paper from the Seghal lab makes an unexpected connection between reactive oxygen species (ROS), lipid metabolism, and sleep. Previous work had shown that neurons release ROS-damaged peroxidated lipids when overexcited or stressed; these lipids are then taken up by glia and temporarily stored in lipid droplets before being metabolized in mitochondria (Liu et al., 2015; Ioannou et al., 2019). Most previous work on this process focused on disease conditions. However, Haynes and colleagues discovered that glial lipid droplet accumulation occurs as part of a daily rhythm: in flies, glia accumulate lipid droplets during the day in response to normal neuronal activity, which are then metabolized by glial mitochondria at night during sleep. The daily transfer of lipids from neurons to glia required neuronal lazarillo (NLaz), a fly apolipoprotein similar to human apolipoprotein E (APOE): knocking down NLaz reduced glial lipid droplet accumulation.
Interestingly, reducing the expression of glial lazarillo (GLaz) resulted in more lipid droplets rather than fewer, which was unexpected. The authors suggest that GLaz may play a function in lipid droplet formation or metabolism within glia, in addition to its role in transporting lipids between cells. This is consistent with recent results from my lab showing that APOE can localize directly to the surface of glial lipid droplets, with APOE knockdown causing larger lipid droplets (Windham et al., 2024). Importantly, reducing either NLaz or GLaz expression resulted in sleep disruption.
This work identifies neuron-glia lipid transport and metabolism as an important new regulator of sleep and raises fascinating questions about how these findings might translate to humans, especially in the context of Alzheimer’s disease. The E4 variant of APOE is the biggest genetic risk factor for developing late-onset Alzheimer’s disease. APOE4 mice were previously found to be more sensitive to sleep disruption than APOE3 mice, with sleep disruption in E4 mice resulting in increased Aβ deposition and tau seeding (Wang et al., 2023). Sleep disturbances are also associated with Alzheimer’s and other neurodegenerative diseases.
This work opens new avenues to explore the mechanistic relationship between APOE, sleep, and AD. Questions remain about how exactly glial lipid metabolism regulates sleep need, or sleep behavior. In addition, it remains to be seen whether human APOE is important for intercellular lipid transfer and/or glial lipid droplet metabolism in the context of sleep, and whether any of these functions are affected by APOE genotype.
References:
Liu L, Zhang K, Sandoval H, Yamamoto S, Jaiswal M, Sanz E, Li Z, Hui J, Graham BH, Quintana A, Bellen HJ. Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration. Cell. 2015 Jan 15;160(1-2):177-90. PubMed.
Ioannou MS, Jackson J, Sheu SH, Chang CL, Weigel AV, Liu H, Pasolli HA, Xu CS, Pang S, Matthies D, Hess HF, Lippincott-Schwartz J, Liu Z. Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity. Cell. 2019 May 30;177(6):1522-1535.e14. Epub 2019 May 23 PubMed.
Windham IA, Powers AE, Ragusa JV, Wallace ED, Zanellati MC, Williams VH, Wagner CH, White KK, Cohen S. APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size. J Cell Biol. 2024 Apr 1;223(4) Epub 2024 Feb 9 PubMed.
Wang C, Nambiar A, Strickland MR, Lee C, Parhizkar S, Moore AC, Musiek ES, Ulrich JD, Holtzman DM. APOE-ε4 synergizes with sleep disruption to accelerate Aβ deposition and Aβ-associated tau seeding and spreading. J Clin Invest. 2023 Jul 17;133(14) PubMed.
View all comments by Sarah CohenWashington University School of Medicine
This is an exciting finding. It builds on work from Hugo Bellen’s lab, which showed that astrocytes can take up lipid droplets from stressed/injured neurons as a neuroprotective mechanism. This new paper provides a novel connection to sleep deprivation, which is bi-directional. This is really interesting.
Our lab recently published data showing that the circadian clock protein REV-ERBalpha can regulate microglial lipid droplets, so both sleep and circadian rhythms may influence lipid droplets in the brain. One implication of this paper is that a possible novel function of sleep (or circadian rhythms) might be to limit activity-induced lipid peroxidation and mitochondrial dysfunction.
This work helps us understand how sleep restriction/disruption can influence brain health and perhaps neurodegenerative pathology, though this was not specifically tested here. We know that people with AD have sleep disruptions, and this study gives us a new idea of why that might happen.
There are a couple of caveats to consider, however. Lipid droplets seem to be very prominent in flies and are seen in a variety of pathological conditions, as well as in cell culture, but they are less common in mouse brain and more difficult to induce in vivo. Moreover, this paper does not examine this phenomenon in any AD models, so the relevance to AD is speculative. However, it is an exciting finding and will certainly spur more research on this topic in mammalian systems and AD models.
View all comments by Erik MusiekUniversity of Wisconsin-Madison
This is a beautiful study with compelling results. That the authors discovered a role for glia in protecting neurons from wake-related oxidative stress is quite unexpected and eye-opening.
The next step will be to test the extent to which this mechanism applies to mammalian sleep. Mice and humans spend 15-20 percent of their total sleep in REM sleep, during which neuronal activity is even higher than in waking. Further, REM sleep accounts for most of the sleep during development. Thus, it will be very interesting to see whether this newly discovered shuttle system is restricted to NREM sleep in mammals.
Also, neurons in several brain regions, including the hippocampus, are equally active in waking as in sleep, and often more active in sleep (for instance, many cells in the dentate gyrus). Thus the “stress” of waking, and therefore the need to sleep, is likely to depend not only on neuronal activity, but also on other factors.
View all comments by Chiara CirelliMake a Comment
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