title: Plasmalogens inhibit APP processing by directly affecting γ-secretase activity in Alzheimer's disease.
abstract: Lipids play an important role as risk or protective factors in Alzheimer's disease (AD). Previously it has been shown that plasmalogens, the major brain phospholipids, are altered in AD. However, it remained unclear whether plasmalogens themselves are able to modulate amyloid precursor protein (APP) processing or if the reduced plasmalogen level is a consequence of AD. Here we identify the plasmalogens which are altered in human AD postmortem brains and investigate their impact on APP processing resulting in Aβ production. All tested plasmalogen species showed a reduction in γ-secretase activity whereas β- and α-secretase activity mainly remained unchanged. Plasmalogens directly affected γ-secretase activity, protein and RNA level of the secretases were unaffected, pointing towards a direct influence of plasmalogens on γ-secretase activity. Plasmalogens were also able to decrease γ-secretase activity in human postmortem AD brains emphasizing the impact of plasmalogens in AD. In summary our findings show that decreased plasmalogen levels are not only a consequence of AD but that plasmalogens also decrease APP processing by directly affecting γ-secretase activity, resulting in a vicious cycle: Aβ reduces plasmalogen levels and reduced plasmalogen levels directly increase γ-secretase activity leading to an even stronger production of Aβ peptides.
authors.affiliation: Experimental Neurology, Saarland University, Kirrbergerstra β e, 66421 Homburg/Saar, Germany.
authors.forename: Tatjana L
authors.initials: TL
authors.lastname: Rothhaar
authors.forename: Sven
authors.initials: S
authors.lastname: Grösgen
authors.forename: Viola J
authors.initials: VJ
authors.lastname: Haupenthal
authors.forename: Verena K
authors.initials: VK
authors.lastname: Burg
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hundsdörfer
authors.forename: Janine
authors.initials: J
authors.lastname: Mett
authors.forename: Matthias
authors.initials: M
authors.lastname: Riemenschneider
authors.forename: Heike S
authors.initials: HS
authors.lastname: Grimm
authors.forename: Tobias
authors.initials: T
authors.lastname: Hartmann
authors.forename: Marcus O W
authors.initials: MO
authors.lastname: Grimm
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010955:Plasmalogens / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D012313:RNA / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D010955:Plasmalogens; D012313:RNA; D053829:Amyloid Precursor Protein Secretases