γ-Secretase modulators show selectivity for γ-secretase-mediated amyloid precursor protein intramembrane processing.
J Cell Mol Med
; 26(3): 880-892, 2022 02.
Article
em En
| MEDLINE
| ID: mdl-34931449
ABSTRACT
The aggregation of ß-amyloid peptide 42 results in the formation of toxic oligomers and plaques, which plays a pivotal role in Alzheimer's disease pathogenesis. Aß42 is one of several Aß peptides, all of Aß30 to Aß43 that are produced as a result of γ-secretase-mediated regulated intramembrane proteolysis of the amyloid precursor protein. γ-Secretase modulators (GSMs) represent a promising class of Aß42-lowering anti-amyloidogenic compounds for the treatment of AD. Gamma-secretase modulators change the relative proportion of secreted Aß peptides, while sparing the γ-secretase-mediated processing event resulting in the release of the cytoplasmic APP intracellular domain. In this study, we have characterized how GSMs affect the γ-secretase cleavage of three γ-secretase substrates, E-cadherin, ephrin type A receptor 4 (EphA4) and ephrin type B receptor 2 (EphB2), which all are implicated in important contexts of cell signalling. By using a reporter gene assay, we demonstrate that the γ-secretase-dependent generation of EphA4 and EphB2 intracellular domains is unaffected by GSMs. We also show that γ-secretase processing of EphA4 and EphB2 results in the release of several Aß-like peptides, but that only the production of Aß-like proteins from EphA4 is modulated by GSMs, but with an order of magnitude lower potency as compared to Aß modulation. Collectively, these results suggest that GSMs are selective for γ-secretase-mediated Aß production.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Precursor de Proteína beta-Amiloide
/
Doença de Alzheimer
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article