Cholesterol, Statins, and Brain Function: A Hypothesis from a Molecular Perspective

  • Shin, Yeon-Kyun (Integrative Bioscience and Biotechnology, POSTECH, Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University)
  • Published : 2009.03.31


There is evidence that cholesterol in the brain plays an important role in the neurotransmitter release. A decrease of the cholesterol level severely hampers the activity of the membrane fusion machinery, thereby inhibiting the release. Meanwhile, the results from several clinical studies suggest that a low cholesterol level is linked to the dysfunction of some brain activities. Because the neurotransmitter release underlies the basic brain function, the combined results lead to a testable hypothesis that the cholesterol-lowering drugs may inhibit the neurotransmitter release at the synapse. Such inhibition of the release could result in impaired brain function for a limited group of people. A molecular basis for the hypothesis is discussed.


  1. Biswas, S., Yin, S. R., Blank, P. S., and Zimmerberg, J. (2008). Cholesterol promotes hemifusion and pore widening in membrane fusion induced by influenza hemagglutinin. J. Gen. Physiol. 131, 503-513
  2. Bjorkhem, I., Andersson, U., Ellis, E., Alvelius, G., Ellegard, L., Diczfalusy, U., Sjovall, J., and Einarsson, C. (2001). From brain to bile. Evidence that conjugation and omega-hydroxylation are important (cerebrosterol) in humans. J. Biol. Chem. 276, 37004-37
  3. Chang, J., Kim, S. A., Lu, X., Su, Z., Kim, S. K., and Shin, Y. K. (2009). Fusion step-specific influence of cholesterol on SNAREmediated membrane fusion. Biophys. J. 96, 1839-1846
  4. Jahn, R., and Scheller, R. H. (2006). SNAREs-engines for membrane fusion. Nat. Rev. Mol. Cell Biol. 7, 631-643
  5. Lang, T., Bruns, D., Wenzel, D., Riedel, D., Holroyd, P., Thiele, C., and Jahn, R. (2001). SNAREs are concentrated in cholesteroldependent clusters that define docking and fusion sites for exocytosis. EMBO J. 20, 2202-2213
  6. Partonen, T., Haukka, J., Virtamo, J., Taylor, P. R., and Lonnqvist, J. (1999). Association of low serum total cholesterol with major depression and suicide. Brit. J. Psychiat. 175, 259-262
  7. Salaun, C., Gould, G. W., and Chamberlain, L. H. (2005). Lipid raft association of SNARE proteins regulates exocytosis in PC12 cells. J. Biol. Chem. 280, 19449-19453
  8. Suarez, E. C. (1999). Relations of trait depression and anxiety to low lipid and lipoprotein concentrations in healthy young adult women. Psychosom. Med. 61, 273-279
  9. Takamori, S., Holt, M., Stenius, K., Lemke, E. A., Gronborg, M., Riedel, D., Urlaub, H., Schenck, S., Brugger, B., Ringler, P., Muller, S. A., Rammner, B., Grater, F., Hub, J. S., De Groot, B. L., Mieskes, G., Moriyama, Y., Klingauf, J., Grubmuller, H., Heuser, J., Wieland, F., and Jahn, R. (2006). Molecular anatomy of a trafficking organelle. Cell 127, 831-846
  10. Tong, J., Borbat, P. P., Freed, J. H., and Shin, Y. K. (2009). A scissors mechanism for stimulation of SNARE-mediated lipid mixing by cholesterol. Proc. Natl. Acad. Sci. USA.
  11. Vance, J. E., Hayashi, H., and Karten, B. (2005). Cholesterol homeostasis in neurons and glial cells, Semin. Cell Dev. Biol. 16, 193-212
  12. Weber, T., Zemelman, B. V., McNew, J. A., Westermann, B., Gmachl, M., Parlati, F., Sollner, T. H., and Rothman, J. E. (1998). SNAREpins: minimal machinery for membrane fusion. Cell 92, 759-772

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