Independent generation of Abeta42 and Abeta38 peptide species by gamma-secretase.
Proteolytic processing of the amyloid precursor protein by beta- and gamma-secretase generates the amyloid-beta (Abeta) peptides, which are principal drug targets in Alzheimer disease therapeutics. gamma-Secretase has imprecise cleavage specificity and generates the most abundant Abeta40 and Abeta42 species together with longer and shorter peptides such as Abeta38. Several mechanisms could explain the production of multiple Abeta peptides by gamma-secretase, including sequential processing of longer into shorter Abeta peptides. A novel class of gamma-secretase modulators (GSMs) that includes some non-steroidal anti-inflammatory drugs has been shown to selectively lower Abeta42 levels without a change in Abeta40 levels. A signature of GSMs is the concomitant increase in shorter Abeta peptides, such as Abeta38, leading to the suggestion that generation of Abeta42 and Abeta38 peptide species by gamma-secretase is coordinately regulated. However, no evidence for or against such a precursor-product relationship has been provided. We have previously shown that stable overexpression of aggressive presenilin-1 (PS1) mutations associated with early-onset familial Alzheimer disease attenuated the cellular response to GSMs, resulting in greatly diminished Abeta42 reductions as compared with wild type PS1. We have now used this model system to investigate whether Abeta38 production would be similarly affected indicating coupled generation of Abeta42 and Abeta38 peptides. Surprisingly, treatment with the GSM sulindac sulfide increased Abeta38 production to similar levels in four different PS1 mutant cell lines as compared with wild type PS1 cells. This was confirmed with the structurally divergent GSMs ibuprofen and indomethacin. Mass spectrometry analysis and high resolution urea gel electrophoresis further demonstrated that sulindac sulfide did not induce detectable compensatory changes in levels of other Abeta peptide species. These data provide evidence that Abeta42 and Abeta38 species can be independently generated by gamma-secretase and argue against a precursor-product relationship between these peptides.
Czirr
Eva
E
Molecular Neuropathology Group, Department of Neuropathology, Heinrich Heine-University, D-40225 Duesseldorf, Germany.
Cottrell
Barbara A
BA
Leuchtenberger
Stefanie
S
Kukar
Thomas
T
Ladd
Thomas B
TB
Esselmann
Hermann
H
Paul
Sabine
S
Schubenel
Robert
R
Torpey
Justin W
JW
Pietrzik
Claus U
CU
Golde
Todd E
TE
Wiltfang
Jens
J
Baumann
Karlheinz
K
Koo
Edward H
EH
Weggen
Sascha
S
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D053764:Presenilin-1; C078639:amyloid beta-protein (1-38); C075222:amyloid beta-protein (1-42); D013467:Sulindac; C025462:sulindac sulfide; D053829:Amyloid Precursor Protein Secretases; D007052:Ibuprofen