title: Docosahexaenoic acid reduces amyloid beta production via multiple pleiotropic mechanisms.
abstract: Alzheimer disease is characterized by accumulation of the β-amyloid peptide (Aβ) generated by β- and γ-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 γ-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 γ-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.
authors.affiliation: Department of Neurodegeneration and Neurobiology, Deutsches Institut für DemenzPrävention, Saarland University, 66421 Homburg, Germany. marcus.grimm@uks.eu
authors.forename: Marcus O W
authors.initials: MO
authors.lastname: Grimm
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuchenbecker
authors.forename: Sven
authors.initials: S
authors.lastname: Grösgen
authors.forename: Verena K
authors.initials: VK
authors.lastname: Burg
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hundsdörfer
authors.forename: Tatjana L
authors.initials: TL
authors.lastname: Rothhaar
authors.forename: Petra
authors.initials: P
authors.lastname: Friess
authors.forename: Martijn C
authors.initials: MC
authors.lastname: de Wilde
authors.forename: Laus M
authors.initials: LM
authors.lastname: Broersen
authors.forename: Botond
authors.initials: B
authors.lastname: Penke
authors.forename: Mária
authors.initials: M
authors.lastname: Péter
authors.forename: László
authors.initials: L
authors.lastname: Vígh
authors.forename: Heike S
authors.initials: HS
authors.lastname: Grimm
authors.forename: Tobias
authors.initials: T
authors.lastname: Hartmann
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000821:Animal Feed; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053764:Presenilin-1 / Q000096:biosynthesis; D012306:Risk
chemical_list: D016564:Amyloid beta-Protein Precursor; D008055:Lipids; D053764:Presenilin-1; D004281:Docosahexaenoic Acids; D002784:Cholesterol; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D051722:ADAM Proteins; D000072198:ADAM17 Protein