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Identifying Links Between Mitochondria, Lipids, and Alzheimer’s Disease
A recent study from the Bellen lab at Baylor College of Medicine and the Duncan Neurological Research Institute identifies novel links between Alzheimer’s disease (AD) risk genes and the build-up of lipids due to mitochondrial dysfunction.
by Dr Matthew Moulton and Dr Hugo Bellen

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease and the number of AD cases is predicted to dramatically increase over the next decades.1 AD is pathologically defined by the aberrant accumulation of proteins, including amyloid β (Aβ) and Tau, and causes a slow cognitive decline including loss of memory.2 While numerous studies, including Genome-Wide Association Studies, have identified genes associated with disease,3,4,5 the underlying mechanism by which these genes contribute to disease remains largely unknown. Disease mechanism discovery is further complicated by the complex interactions between different brain cell types, including neurons and glia. Genes may be turned on (expressed) in some cells and not in others. Hence, determination of the cell-specific function of genes may be critical for delineating disease aetiology.

Dr. Matt Moulton in Dr. Hugo Bellen’s lab has been studying the molecular mechanisms that underlie AD. Using the fruit fly, the lab has identified dozens of genes important for neuronal health and function, including genes that are required for proper mitochondrial function.6,7,8 Alterations in some of the mitochondrial proteins causes a toxic build-up of oxygen radicals called Reactive Oxygen Species (ROS). ROS accumulation in neurons activates the production of lipids, which become peroxidised in the presence of ROS. Excess lipid accumulation and peroxidation is toxic to cells and neurons appear to be particularly vulnerable to these molecules. The Bellen Lab demonstrated that peroxidised lipids originating from neurons are mobilised to neighbouring glial cells where they are sequestered into organelles called lipid droplets (LD). Moving these toxic molecules into glial LD prevents neurodegeneration and disrupting this process accelerates neurodegeneration.6,9,10

The shuttling of peroxidised lipids from neurons to glia requires, among others, a gene known to be associated with AD, called APOE. The APOE gene encodes a lipoprotein that helps move lipids between cells and tissues. Within the human population, there exists variation in the APOE gene with some variants having no effect (APOE3) or a protective effect (APOE2) on the development of AD. However, one variant (APOE4) is the strongest known genetic risk factor for the development of AD.11 In the fly, APOE2 and APOE3 can productively participate in the process of lipid transfer between neurons and glia, but APOE4 is defective in this process.9 This suggests that APOE4 might contribute to AD development by inhibiting the efficient transfer of toxic lipids between neurons and glia.

In a recent study, the Bellen Lab identified genes in the glial LD formation pathway that include AD risk genes.10 The lab identified cell-specific roles for AD risk genes in the formation of LD in glia. Specifically, loss of ABCA1 and ABCA7 in neurons, but not glia, prevented glial LD synthesis and promoted ROS-induced neurodegeneration. These genes are involved in lipid transfer across membranes and facilitate the lipidation of extracellular APOE and other lipoproteins.12,13

It was also discovered that genes involved in recognising and taking up lipidated APOE are required in glia, but not neurons, for proper LD formation. Loss of these genes in glia also led to ROS-induced neurodegeneration. Further, the requirement for the proteins encoded by these genes in LD formation is also observed in rat neurons/glia suggesting that LD formation pathway is conserved from flies to vertebrates.9,10,14

These findings strongly argue in favour of glial LD formation in preventing neurodegeneration and AD. Support for this idea was also found by the authors when they genetically expressed a small protein that has been shown to activate ABCA1 to increase APOE lipidation.15,16,17 In flies that express human APOE4 and are subjected to neuronal ROS, the protein restored glial LD formation and prevented APOE4-associated ROS-induced neurodegeneration. Together, these findings implicate AD risk genes in playing a neuroprotective role by promoting glial LD formation to sequester peroxidated lipids. Their loss or dysfunction may lead to disease by preventing ROS mitigation via glial LD formation. Hence, this study identifies a direct connection between mitochondrial ROS production, lipid accumulation, and neurodegeneration.

The authors went on to demonstrate that there is an interaction between ROS and one hallmark of AD, Aβ. In the fruit fly, neither human Aβ nor low levels of ROS alone induce neurodegeneration in young flies, but when low ROS and Aβ are both present, rapid neurodegeneration occurs in young flies. Activation of ROS in mouse models of human Aβ expression confirms that Aβ accumulation is worsened by the presence of ROS. These findings implicate ROS in exacerbating AD phenotypes. Importantly, the proteins that are involved in LD formation also participate in the clearing of the neurotoxic Aβ protein. This is particularly important for our understanding of AD aetiology since ROS production is elevated with age and elevated brain ROS is commonly found in AD patients.18,19,20

Altogether, these findings indicate that ROS production, by defective mitochondria, induces lipid peroxidation and enhances Aβ accumulation culminating in neurodegeneration. Importantly, feeding flies a potent ROS-mitigating antioxidant compound (N-acetylcysteine amide or NACA) prevented neurodegeneration, even when key LD formation genes are lost. Hence, strategies aimed at preventing ROS accumulation may prove therapeutically fruitful for AD by alleviating ROS-mediated neurotoxicity and by diminishing Aβ accumulation. Antioxidant therapy for AD and other neurodegenerative disorders has been met with mixed success, but the authors argue that an earlier intervention using antioxidants that can better target brain tissue, such as NACA, should be tested in individuals that carry genetic risk variants for AD, like APOE4.

In addition to these important findings, this study highlights the utility of the fruit fly for human disease research.21,22,23 The early work in the Bellen lab to identify genes important for neurodegeneration led to the discovery of the gene sicily, which, when mutated, led to the glial LD phenotype which initiated these investigations.8 Mutations in the human homolog of sicily, NDUFAF6, have been identified as a cause of a rare neurodevelopmental disorder, Leigh Syndrome.24 The work in the Bellen Lab connected the phenotypes associated with the loss of sicily to AD6,9 and recently NDUFAF6 was identified by human genomic studies as a putative risk factor for AD.3 Thus, the use of the fruit fly to study genes implicated in rare diseases have shed valuable insights for common human neurodegenerative disease, like AD.

References

  1. Nichols, E., & Vos, T. (2020). Estimating the global mortality from Alzheimer’s disease and other dementias: A new method and results from the Global Burden of Disease study 2019. Alzheimer’s & Dementia, 16(S10), e042236. https://doi.org/10.1002/ALZ.042236
  2. Deture, M. A., & Dickson, D. W. (2019). The neuropathological diagnosis of Alzheimer’s disease. Molecular Neurodegeneration 2019 14:1, 14(1), 1–18. https://doi.org/10.1186/S13024-019-0333-5
  3. Bellenguez, C., Küçükali, F., Jansen, I., V, A., S, M.-G., N, A., … Jordi. (2020). New insights on the genetic etiology of Alzheimer’s and related dementia. MedRxiv. https://doi.org/10.1101/2020.10.01.20200659
  4. Kunkle, B. W., Grenier-Boley, B., Sims, R., Bis, J. C., Damotte, V., Naj, A. C., … Pericak-Vance, M. A. (2019). Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nature Genetics, 51(3), 414–430. https://doi.org/10.1038/s41588-019-0358-2
  5. Lambert, J.-C., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., … Amouyel, P. (2013). Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nature Genetics, 45(12), 1452–1458. https://doi.org/10.1038/ng.2802
  6. Liu, L., Zhang, K., Sandoval, H., Yamamoto, S., Jaiswal, M., Sanz, E., … Bellen, H. J. (2015). Glial Lipid Droplets and ROS Induced by Mitochondrial Defects Promote Neurodegeneration. Cell, 160(1–2), 177–190. https://doi.org/10.1016/j.cell.2014.12.019
  7. Yamamoto, S., Jaiswal, M., Charng, W. L., Gambin, T., Karaca, E., Mirzaa, G., … Bellen, H. J. (2014). A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases. Cell, 159(1), 200–214. https://doi.org/10.1016/j.cell.2014.09.002
  8. Zhang, K., Li, Z., Jaiswal, M., Bayat, V., Xiong, B., Sandoval, H., … Bellen, H. J. (2013). The C8ORF38 homologue Sicily is a cytosolic chaperone for a mitochondrial complex I subunit. The Journal of Cell Biology, 200(6), 807–820. https://doi.org/10.1083/jcb.201208033
  9. Liu, L., MacKenzie, K. R., Putluri, N., Maleti´c-Savati´c, M., & Bellen, H. J. (2017). The Glia-Neuron Lactate Shuttle and Elevated ROS Promote Lipid Synthesis in Neurons and Lipid Droplet Accumulation in Glia via APOE/D. Cell Metabolism, 26(5), 1–19. https://doi.org/10.1016/j.cmet.2017.08.024
  10. Moulton, M. J., Barish, S., Ralhan, I., Chang, J., Goodman, L. D., Harland, J. G., … Bellen, H. J. (2021). Neuronal ROS-induced glial lipid droplet formation is altered by loss of Alzheimer’s disease–associated genes. Proceedings of the National Academy of Sciences, 118(52), e2112095118. https://doi.org/10.1073/pnas.2112095118
  11. Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C. C., & Bu, G. (2019). Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nature Reviews Neurology 2019 15:9, 15(9), 501–518. https://doi.org/10.1038/s41582-019-0228-7
  12. Cavelier, C., Lorenzi, I., Rohrer, L., & von Eckardstein, A. (2006). Lipid efflux by the ATP-binding cassette transporters ABCA1 and ABCG1. Biochimica et Biophysica Acta, 1761(7), 655–666. https://doi.org/10.1016/J.BBALIP.2006.04.012
  13. Krimbou, L., Denis, M., Haidar, B., Carrier, M., Marcil, M., & Genest, J. (2004). Molecular interactions between apoE and ABCA1: Impact on apoE lipidation. Journal of Lipid Research, 45(5), 839–848. https://doi.org/10.1194/jlr.M300418-JLR200
  14. Ioannou, M. S., Jackson, J., Sheu, S.-H., Chang, C.-L., Weigel, A. V., Liu, H., … Liu, Z. (2019). Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity. Cell, 177(6), 1522-1535.e14. https://doi.org/10.1016/j.cell.2019.04.001
  15. Boehm-Cagan, A., Bar, R., Harats, D., Shaish, A., Levkovitz, H., Bielicki, J. K., … Michaelson, D. M. (2016). Differential Effects of apoE4 and Activation of ABCA1 on Brain and Plasma Lipoproteins. PLoS ONE, 11(11), 1–17. https://doi.org/10.1371/journal.pone.0166195
  16. Boehm-Cagan, A., Bar, R., Liraz, O., Bielicki, J. K., Johansson, J. O., & Michaelson, D. M. (2016). ABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies. Journal of Alzheimer’s Disease, 54(3), 1219–1233. https://doi.org/10.3233/JAD-160467
  17. Boehm-Cagan, A., & Michaelson, D. M. (2014). Reversal of apoE4-Driven Brain Pathology and Behavioral Deficits by Bexarotene. Journal of Neuroscience, 34(21), 7293–7301. https://doi.org/10.1523/JNEUROSCI.5198-13.2014
  18. Butterfield, D. A. (2020, December 1). Brain lipid peroxidation and alzheimer disease: Synergy between the Butterfield and Mattson laboratories. Ageing Research Reviews, Vol. 64, pp. 1568–1637. https://doi.org/10.1016/j.arr.2020.101049
  19. Grimm, A., & Eckert, A. (2017). Brain aging and neurodegeneration: from a mitochondrial point of view. Journal of Neurochemistry, 143(4), 418–431. https://doi.org/10.1111/jnc.14037
  20. Peña-Bautista, C., López-Cuevas, R., Cuevas, A., Baquero, M., & Cháfer-Pericás, C. (2019). Lipid peroxidation biomarkers correlation with medial temporal atrophy in early Alzheimer Disease. Neurochemistry International, 129, 104519. https://doi.org/10.1016/j.neuint.2019.104519
  21. Link, N., & Bellen, H. J. (2020). Using Drosophila to drive the diagnosis and understand the mechanisms of rare human diseases. Development (Cambridge, England), 147(21), 1–7. https://doi.org/10.1242/dev.191411
  22. Moulton, M. J., & Letsou, A. (2016). Modeling congenital disease and inborn errors of development in Drosophila melanogaster. DMM Disease Models and Mechanisms, 9(3), 253–269. https://doi.org/10.1242/dmm.023564
  23. Wangler, M. F., Yamamoto, S., Chao, H. T., Posey, J. E., Westerfield, M., Postlethwait, J., … Palmer, C. G. (2017). Model organisms facilitate rare disease diagnosis and therapeutic research. Genetics, 207(1), 9–27. https://doi.org/10.1534/genetics.117.203067
  24. Baide-Mairena, H., Gaudó, P., Marti-Sánchez, L., Emperador, S., Sánchez-Montanez, A., Alonso-Luengo, O., … Pérez-Dueñas, B. (2019). Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood. Molecular Genetics and Metabolism, 126(3), 250–258. https://doi.org/10.1016/J.YMGME.2019.01.001

About the Authors

Dr. Matthew J. Moulton, Ph.D., Baylor College of Medicine, Duncan Neurological Research Institute at Texas Children’s Hospital, postdoctoral fellow and leading author.

Dr. Hugo J. Bellen, DVM, Ph.D., Baylor College of Medicine, Duncan Neurological Research Institute at Texas Children’s Hospital, professor and principle investigator.

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