APOE4 impairs oxidative phosphorylation and cholesterol metabolism in Alzheimer’s Disease
DOI:
https://doi.org/10.47611/jsrhs.v13i4.8188Keywords:
Alzheimer's Disease, APOE, mitochondria, statin, oxidative phosphorylation, cholesterol metabolismAbstract
Alzheimer’s disease (AD) is strongly associated with mitochondrial dysfunction, especially in the presence of the APOE4 allele. Here I review recent research on the connection between APOE4 and impairment of mitochondrial oxidative phosphorylation (OXPHOS). In APOE4 carriers, decreased basal respiration rates suggest reduced mitochondrial respiration, and studies have reported downregulation of mitochondrial proteins critical for OXPHOS function. Furthermore, cytotoxic APOE4 fragments in neurons inhibit OXPHOS by decreasing mitochondrial membrane potential. In addition, APOE4-induced cholesterol accumulation in astrocytes and oligodendrocytes correlates with mitochondrial OXPHOS impairment. Lastly, I highlight the potential of statins, which are known to lower cholesterol levels, as a therapeutic treatment. Given the crucial role of mitochondrial dysfunction in AD pathology, a better understanding of how APOE4 affects mitochondrial OXPHOS would aid in the development of new strategies to slow down AD progression.
Downloads
References or Bibliography
Barber, R. C. (2012). The genetics of Alzheimer's disease. Scientifica (Cairo), 2012, 246210. https://doi.org/10.6064/2012/246210
Blanchard, J. W., Akay, L. A., Davila-Velderrain, J., von Maydell, D., Mathys, H., Davidson, S. M., Effenberger, A., Chen, C. Y., Maner-Smith, K., Hajjar, I., Ortlund, E. A., Bula, M., Agbas, E., Ng, A., Jiang, X., Kahn, M., Blanco-Duque, C., Lavoie, N., Liu, L., . . . Tsai, L. H. (2022). APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature, 611(7937), 769-779. https://doi.org/10.1038/s41586-022-05439-w
Blumenfeld, J., Yip, O., Kim, M. J., & Huang, Y. (2024). Cell type-specific roles of APOE4 in Alzheimer disease. Nat Rev Neurosci, 25(2), 91-110. https://doi.org/10.1038/s41583-023-00776-9
Chang, S., ran Ma, T., Miranda, R. D., Balestra, M. E., Mahley, R. W., & Huang, Y. (2005). Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. Proc Natl Acad Sci U S A, 102(51), 18694-18699. https://doi.org/10.1073/pnas.0508254102
Cooper, G. M. (2000). The Mechanism of Oxidative Phosphorylation. In The Cell: A Molecular Approach (2nd ed.). Sunderland (MA): Sinauer Associates. https://www.ncbi.nlm.nih.gov/books/NBK9885/
DeTure, M. A., & Dickson, D. W. (2019). The neuropathological diagnosis of Alzheimer's disease. Mol Neurodegener, 14(1), 32. https://doi.org/10.1186/s13024-019-0333-5
Evans, M. A., & Golomb, B. A. (2009). Statin-associated adverse cognitive effects: survey results from 171 patients. Pharmacotherapy, 29(7), 800-811. https://doi.org/10.1592/phco.29.7.800
Farmer, B. C., Williams, H. C., Devanney, N. A., Piron, M. A., Nation, G. K., Carter, D. J., Walsh, A. E., Khanal, R., Young, L. E. A., Kluemper, J. C., Hernandez, G., Allenger, E. J., Mooney, R., Golden, L. R., Smith, C. T., Brandon, J. A., Gupta, V. A., Kern, P. A., Gentry, M. S., . . . Johnson, L. A. (2021). APOEpsilon4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis. Mol Neurodegener, 16(1), 62. https://doi.org/10.1186/s13024-021-00483-y
Farrer, L. A., Cupples, L. A., Haines, J. L., Hyman, B., Kukull, W. A., Mayeux, R., Myers, R. H., Pericak-Vance, M. A., Risch, N., & van Duijn, C. M. (1997). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA, 278(16), 1349-1356. https://www.ncbi.nlm.nih.gov/pubmed/9343467
Feingold, K. R. (2000). Cholesterol Lowering Drugs. In K. R. Feingold, B. Anawalt, M. R. Blackman, A. Boyce, G. Chrousos, E. Corpas, W. W. de Herder, K. Dhatariya, K. Dungan, J. Hofland, S. Kalra, G. Kaltsas, N. Kapoor, C. Koch, P. Kopp, M. Korbonits, C. S. Kovacs, W. Kuohung, B. Laferrere, M. Levy, E. A. McGee, R. McLachlan, M. New, J. Purnell, R. Sahay, A. S. Shah, F. Singer, M. A. Sperling, C. A. Stratakis, D. L. Trence, & D. P. Wilson (Eds.), Endotext. https://www.ncbi.nlm.nih.gov/pubmed/27809434
Kish, S. J., Bergeron, C., Rajput, A., Dozic, S., Mastrogiacomo, F., Chang, L. J., Wilson, J. M., DiStefano, L. M., & Nobrega, J. N. (1992). Brain cytochrome oxidase in Alzheimer's disease. J Neurochem, 59(2), 776-779. https://doi.org/10.1111/j.1471-4159.1992.tb09439.x
Knoferle, J., Yoon, S. Y., Walker, D., Leung, L., Gillespie, A. K., Tong, L. M., Bien-Ly, N., & Huang, Y. (2014). Apolipoprotein E4 produced in GABAergic interneurons causes learning and memory deficits in mice. J Neurosci, 34(42), 14069-14078. https://doi.org/10.1523/JNEUROSCI.2281-14.2014
Lee, H., Cho, S., Kim, M. J., Park, Y. J., Cho, E., Jo, Y. S., Kim, Y. S., Lee, J. Y., Thoudam, T., Woo, S. H., Lee, S. I., Jeon, J., Lee, Y. S., Suh, B. C., Yoon, J. H., Go, Y., Lee, I. K., & Seo, J. (2023). ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes. Cell Rep, 42(10), 113183. https://doi.org/10.1016/j.celrep.2023.113183
Mahley, R. W. (1988). Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science, 240(4852), 622-630. https://doi.org/10.1126/science.3283935
Mahley, R. W. (2023). Apolipoprotein E4 targets mitochondria and the mitochondria-associated membrane complex in neuropathology, including Alzheimer's disease. Curr Opin Neurobiol, 79, 102684. https://doi.org/10.1016/j.conb.2023.102684
Michikawa, M., Fan, Q. W., Isobe, I., & Yanagisawa, K. (2000). Apolipoprotein E exhibits isoform-specific promotion of lipid efflux from astrocytes and neurons in culture. J Neurochem, 74(3), 1008-1016. https://doi.org/10.1046/j.1471-4159.2000.0741008.x
Nakamura, T., Watanabe, A., Fujino, T., Hosono, T., & Michikawa, M. (2009). Apolipoprotein E4 (1-272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells. Mol Neurodegener, 4, 35. https://doi.org/10.1186/1750-1326-4-35
Orr, A. L., Kim, C., Jimenez-Morales, D., Newton, B. W., Johnson, J. R., Krogan, N. J., Swaney, D. L., & Mahley, R. W. (2019). Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function. J Alzheimers Dis, 68(3), 991-1011. https://doi.org/10.3233/JAD-181184
Osellame, L. D., Blacker, T. S., & Duchen, M. R. (2012). Cellular and molecular mechanisms of mitochondrial function. Best Pract Res Clin Endocrinol Metab, 26(6), 711-723. https://doi.org/10.1016/j.beem.2012.05.003
Ottinger, E. A., Kao, M. L., Carrillo-Carrasco, N., Yanjanin, N., Shankar, R. K., Janssen, M., Brewster, M., Scott, I., Xu, X., Cradock, J., Terse, P., Dehdashti, S. J., Marugan, J., Zheng, W., Portilla, L., Hubbs, A., Pavan, W. J., Heiss, J., Vite, C. H., . . . McKew, J. C. (2014). Collaborative development of 2-hydroxypropyl-beta-cyclodextrin for the treatment of Niemann-Pick type C1 disease. Curr Top Med Chem, 14(3), 330-339. https://doi.org/10.2174/1568026613666131127160118
Rajan, K. B., McAninch, E. A., Wilson, R. S., Dhana, A., Evans-Lacko, S., & Evans, D. A. (2024). Statin Initiation and Risk of Incident Alzheimer Disease and Cognitive Decline in Genetically Susceptible Older Adults. Neurology, 102(7), e209168. https://doi.org/10.1212/WNL.0000000000209168
Schreiner, B., & Ankarcrona, M. (2017). Isolation of Mitochondria-Associated Membranes (MAM) from Mouse Brain Tissue. Methods Mol Biol, 1567, 53-68. https://doi.org/10.1007/978-1-4939-6824-4_5
Silva, D. F., Selfridge, J. E., Lu, J., E, L., Roy, N., Hutfles, L., Burns, J. M., Michaelis, E. K., Yan, S., Cardoso, S. M., & Swerdlow, R. H. (2013). Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines. Hum Mol Genet, 22(19), 3931-3946. https://doi.org/10.1093/hmg/ddt247
Torrandell-Haro, G., Branigan, G. L., Vitali, F., Geifman, N., Zissimopoulos, J. M., & Brinton, R. D. (2020). Statin therapy and risk of Alzheimer's and age-related neurodegenerative diseases. Alzheimers Dement (N Y), 6(1), e12108. https://doi.org/10.1002/trc2.12108
Vercellino, I., & Sazanov, L. A. (2022). The assembly, regulation and function of the mitochondrial respiratory chain. Nat Rev Mol Cell Biol, 23(2), 141-161. https://doi.org/10.1038/s41580-021-00415-0
Wang, W., Zhao, F., Ma, X., Perry, G., & Zhu, X. (2020). Mitochondria dysfunction in the pathogenesis of Alzheimer's disease: recent advances. Mol Neurodegener, 15(1), 30. https://doi.org/10.1186/s13024-020-00376-6
Wu, L., Zhang, X., & Zhao, L. (2018). Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention. J Neurosci, 38(30), 6665-6681. https://doi.org/10.1523/JNEUROSCI.2262-17.2018
Zorova, L. D., Popkov, V. A., Plotnikov, E. Y., Silachev, D. N., Pevzner, I. B., Jankauskas, S. S., Babenko, V. A., Zorov, S. D., Balakireva, A. V., Juhaszova, M., Sollott, S. J., & Zorov, D. B. (2018). Mitochondrial membrane potential. Anal Biochem, 552, 50-59. https://doi.org/10.1016/j.ab.2017.07.009
Published
How to Cite
Issue
Section
Copyright (c) 2024 Hao-Yu Gan; Joseph Cichon
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Copyright holder(s) granted JSR a perpetual, non-exclusive license to distriute & display this article.
