title: Signature amyloid β profiles are produced by different γ-secretase complexes.
abstract: γ-Secretase complexes are involved in the generation of amyloid-β (Aβ) in the brain. Therefore, γ-secretase has been proposed as a potential therapeutic target in Alzheimer disease (AD). Targeting γ-secretase activity in AD requires the pharmacological dissociation of the processing of physiological relevant substrates and the generation of "toxic" Aβ. Previous reports suggest the differential targeting of γ-secretase complexes, based on their subunit composition, as a valid strategy. However, little is known about the biochemical properties of the different complexes, and key questions regarding their Aβ product profiles should be first addressed. Here, we expressed, purified, and analyzed, under the same conditions, the endopeptidase and carboxypeptidase-like activities of the four γ-secretase complexes present in humans. We find that the nature of the catalytic subunit in the complex affects both activities. Interestingly, PSEN2 complexes discriminate between the Aβ40 and Aβ38 production lines, indicating that Aβ generation in one or the other pathway can be dissociated. In contrast, the APH1 subunit mainly affects the carboxypeptidase-like activity, with APH1B complexes favoring the generation of longer Aβ peptides. In addition, we determined that expression of a single human γ-secretase complex in cell lines retains the intrinsic attributes of the protease while present in the membrane, providing validation for the in vitro studies. In conclusion, our data show that each γ-secretase complex produces a characteristic Aβ signature. The qualitative and quantitative differences between different γ-secretase complexes could be used to advance drug development in AD and other disorders.
authors: From the Center for the Biology of Disease, Flemish Institute for Biology (VIB), 3000 Leuven, Belgium.
authors: Hermien
authors: H
authors: Acx
authors: Lucía
authors: L
authors: Chávez-Gutiérrez
authors: Lutgarde
authors: L
authors: Serneels
authors: Sam
authors: S
authors: Lismont
authors: Manasi
authors: M
authors: Benurwar
authors: Nadav
authors: N
authors: Elad
authors: Bart
authors: B
authors: De Strooper
mesh_terms: D000544:Alzheimer Disease / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D010450:Endopeptidases; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D053766:Presenilin-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053766:Presenilin-2; C078639:amyloid beta-protein (1-38); C078592:amyloid beta-protein (1-40); C475155:APH1B protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases
keywords: Alzheimer Disease; Amyloid Beta; Amyloid Precursor Protein; Enzyme Mechanisms; Gamma-Secretase; Neurobiology; Secretases