title: Plasmalogen synthesis is regulated via alkyl-dihydroxyacetonephosphate-synthase by amyloid precursor protein processing and is affected in Alzheimer's disease.
abstract: Lipids play an important role as risk or protective factors in Alzheimer's disease, which is characterized by amyloid plaques composed of aggregated amyloid-beta. Plasmalogens are major brain lipids and controversially discussed to be altered in Alzheimer's disease (AD) and whether changes in plasmalogens are cause or consequence of AD pathology. Here, we reveal a new physiological function of the amyloid precursor protein (APP) in plasmalogen metabolism. The APP intracellular domain was found in vivo and in vitro to increase the expression of the alkyl-dihydroxyacetonephosphate-synthase (AGPS), a rate limiting enzyme in plasmalogen synthesis. Alterations in APP dependent changes of AGPS expression result in reduced protein and plasmalogen levels. Under the pathological situation of AD, increased amyloid-beta level lead to increased reactive oxidative species production, reduced AGPS protein and plasmalogen level. Accordingly, phosphatidylethanol plasmalogen was decreased in the frontal cortex of AD compared to age matched controls. Our findings elucidate that plasmalogens are decreased as a consequence of AD and regulated by APP processing under physiological conditions.
authors.affiliation: Neurodegeneration and Neurobiology, Deutsches Institut für DemenzPrävention (DIDP), 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: Tatjana L
authors.initials: TL
authors.lastname: Rothhaar
authors.forename: Sven
authors.initials: S
authors.lastname: Grösgen
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hundsdörfer
authors.forename: Verena K
authors.initials: VK
authors.lastname: Burg
authors.forename: Petra
authors.initials: P
authors.lastname: Friess
authors.forename: Ulrike
authors.initials: U
authors.lastname: Müller
authors.forename: Heike S
authors.initials: HS
authors.lastname: Grimm
authors.forename: Mathias
authors.initials: M
authors.lastname: Riemenschneider
authors.forename: Tobias
authors.initials: T
authors.lastname: Hartmann
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D010955:Plasmalogens / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010955:Plasmalogens; D017382:Reactive Oxygen Species; D019883:Alkyl and Aryl Transferases; C019654:alkylglycerone-phosphate synthase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase