Docosahexaenoic acid reduces amyloid β production via multiple pleiotropic mechanisms

Marcus O.W. Grimm, Johanna Kuchenbecker, Sven Grosgen, Verena K. Burg, Benjamin Hundsdorfer, Tatjana L. Rothhaar, Petra Friess, Martijn C. De Wilde, Laus M. Broersen, Botond Penke, Maria Peter, Laszlo Vígh, Heike S. Grimm, Tobias Hartmann

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128 Citations (Scopus)


Alzheimer disease is characterized by accumulation of the β-amyloid peptide (Aβ) generated by β-and y-secretase processing of the amyloid precursor protein (APP). The intake of the polyunsaturated fatty acid docosahexaenoic acid (DHA) has been associated with decreased amyloid deposition and a reduced risk in Alzheimer disease in several epidemiological trials; however, the exact underlying molecular mechanism remains to be elucidated. Here, we systematically investigate the effect of DHA on amyloidogenic and nonamyloidogenic APP processing and the potential cross-links to cholesterol metabolism in vivo and in vitro. DHA reduces amyloidogenic processing by decreasing β-and y-secretase activity, whereas the expression and protein levels of BACE1 and presenilin1 remain unchanged. In addition, DHA increases protein stability of α-secretase resulting in increased nonamyloidogenic processing. Besides the known effect of DHA to decrease cholesterol de novo synthesis, we found cholesterol distribution in plasma membrane to be altered. In the presence of DHA, cholesterol shifts from raft to non-raft domains, and this is accompanied by a shift in y-secretase activity and presenilin1 protein levels. Taken together, DHA directs amyloidogenic processing of APP toward nonamyloidogenic processing, effectively reducing Aβ release. DHA has a typical pleiotropic effect; DHA-mediated Aβ reduction is not the consequence of a single major mechanism but is the result of combined multiple effects.

Original languageEnglish
Pages (from-to)14028-14039
Number of pages12
JournalJournal of Biological Chemistry
Issue number16
Publication statusPublished - ápr. 22 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Grimm, M. O. W., Kuchenbecker, J., Grosgen, S., Burg, V. K., Hundsdorfer, B., Rothhaar, T. L., Friess, P., De Wilde, M. C., Broersen, L. M., Penke, B., Peter, M., Vígh, L., Grimm, H. S., & Hartmann, T. (2011). Docosahexaenoic acid reduces amyloid β production via multiple pleiotropic mechanisms. Journal of Biological Chemistry, 286(16), 14028-14039.