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The composition of the γ-secretase complex defines its Aβ product profile
Molecular Neurodegeneration volume 8, Article number: P2 (2013)
Aβ peptides accumulate and aggregate in the brain of patients suffering from Alzheimer’s disease (AD). Since γ-secretase is the final protease involved in the production of Aβ peptides, it has been proposed as a potential drug target in AD. This multiprotein complex consists of four essential subunits: presenilin (PSEN), nicastrin (NCT), anterior pharynx defective (APH1) and presenilin enhancer 2 (PEN-2), which assemble in a 1:1:1:1 stoichiometry. As two PSEN genes and two APH1 genes exist, at least four different γ-secretase complexes exist. Previous studies suggest that this structural heterogeneity has functional implications . Here, we show that the subunit composition of the γ-secretase complex determines its activity and we unravel the biochemical mechanism underlying these differences.
Materials and methods
The activity of purified γ-secretase complexes was assessed in an in vitro assay. The endopeptidase and carboxypeptidase-like activities of the γ-secretase complex were evaluated by measuring the de novo generation of amyloid precursor protein intracellular domain (AICD) or the conversion of Aβ43/Aβ42 into Aβ40/Aβ38, respectively . To confirm our results on a cell based level, we measured the Aβ peptides secreted in the medium by mouse embryonic fibroblasts expressing only one type of γ-secretase complex.
PSEN2 containing complexes lower the overall activity of the γ-secretase, relative to the corresponding PSEN1 complexes. In contrast, APH1B-containing γ-secretase complexes did not change endopeptidase activity levels but reduce the efficiency of the carboxypeptidase-like activity, when compared to the corresponding APH1 A-containing complexes. Interestingly, the effect observed in the APH1B-containing γ-secretase complexes is similar to the reported familial AD PSEN mutations(2) and suggests that APH1B-containing complexes are characterized by a more rapid product release, which explains why more longer and aggregation prone Aβ peptides are generated by APH1B complexes.
Taken all together our results show that the composition of the γ-secretase complex defines distinctive Aβ product profiles and supports that specific targeting of APH1B-containing γ-secretase complexes may represent a valid strategy in Alzheimer’s disease therapy.
Serneels L, Van Biervliet J, Craessaerts K, Dejaegere T, Horré K, Van Houtvin T, et al: Gamma-Secretase Heterogeneity in the Aph1 Subunit Relevance for Alzheimer’s Disease. Science. 2009, 324: 639-642. 10.1126/science.1171176.
Chavez-Gutierrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M, Borgers M, et al: The mechanism of [gamma]-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012, 31: 2261-2274. 10.1038/emboj.2012.79.
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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Acx, H., Gutiérrez, L.C., Serneels, L. et al. The composition of the γ-secretase complex defines its Aβ product profile. Mol Neurodegeneration 8 (Suppl 1), P2 (2013). https://doi.org/10.1186/1750-1326-8-S1-P2
- Amyloid Precursor Protein
- Mouse Embryonic Fibroblast
- Potential Drug Target
- Endopeptidase Activity