title: Generation of Abeta38 and Abeta42 is independently and differentially affected by familial Alzheimer disease-associated presenilin mutations and gamma-secretase modulation.
abstract: Alzheimer disease amyloid beta-peptide (Abeta) is generated via proteolytic processing of the beta-amyloid precursor protein by beta- and gamma-secretase. Gamma-secretase can be blocked by selective inhibitors but can also be modulated by a subset of non-steroidal anti-inflammatory drugs, including sulindac sulfide. These drugs selectively reduce the generation of the aggregation-prone 42-amino acid Abeta(42) and concomitantly increase the levels of the rather benign Abeta(38). Here we show that Abeta(42) and Abeta(38) generation occur independently from each other. The amount of Abeta(42) produced by cells expressing 10 different familial Alzheimer disease (FAD)-associated mutations in presenilin (PS) 1, the catalytic subunit of gamma-secretase, appeared to correlate with the respective age of onset in patients. However, Abeta(38) levels did not show a negative correlation with the age of onset. Modulation of gamma-secretase activity by sulindac sulfide reduced Abeta(42) in the case of wild type PS1 and two FAD-associated PS1 mutations (M146L and A285V). The remaining eight PS1 FAD mutants showed either no reduction of Abeta(42) or only rather subtle effects. Strikingly, even the mutations that showed no effect on Abeta(42) levels allowed a robust increase of Abeta(38) upon treatment with sulindac sulfide. Similar observations were made for fenofibrate, a compound known to increase Abeta(42) and to decrease Abeta(38). For mutants that predominantly produce Abeta(42), the ability of fenofibrate to further increase Abeta(42) levels became diminished, whereas Abeta(38) levels were altered to varying extents for all mutants analyzed. Thus, we conclude that Abeta(38) and Abeta(42) production do not depend on each other. Using an independent non-steroidal anti-inflammatory drug derivative, we obtained similar results for PS1 as well as for PS2. These in vitro results were confirmed by in vivo experiments in transgenic mice expressing the PS2 N141I FAD mutant. Our findings therefore have strong implications on the selection of transgenic mouse models used for screening of the Abeta(42)-lowering capacity of gamma-secretase modulators. Furthermore, human patients with certain PS mutations may not respond to gamma-secretase modulators.
authors.affiliation: Center for Integrated Protein Science Munich and Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Ludwig Maximilians University, 80336 Munich, Germany.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Page
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Baumann
authors.forename: Masanori
authors.initials: M
authors.lastname: Tomioka
authors.forename: Blanca I
authors.initials: BI
authors.lastname: Pérez-Revuelta
authors.forename: Akio
authors.initials: A
authors.lastname: Fukumori
authors.forename: Helmut
authors.initials: H
authors.lastname: Jacobsen
authors.forename: Alexander
authors.initials: A
authors.lastname: Flohr
authors.forename: Thomas
authors.initials: T
authors.lastname: Luebbers
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
authors.forename: Harald
authors.initials: H
authors.lastname: Steiner
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides; D000818:Animals; D001921:Brain / Q000502:physiology; D002460:Cell Line; D006801:Humans; D007668:Kidney / Q000196:embryology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010446:Peptide Fragments; D053764:Presenilin-1 / Q000235:genetics*; D053766:Presenilin-2 / Q000235:genetics*; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; C075222:amyloid beta-protein (1-42); C493515:amyloid beta-protein (25-38); D053829:Amyloid Precursor Protein Secretases