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  • Weber, Tobias A (author)

γ-Secretase modulators show selectivity for γ-secretase-mediated amyloid precursor protein intramembrane processing.

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • 2021-12-20
  • Wiley,2022

Numbers

  • LIBRIS-ID:oai:gup.ub.gu.se/312046
  • https://gup.ub.gu.se/publication/312046URI
  • https://doi.org/10.1111/jcmm.17146DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:148380416URI

Supplementary language notes

  • Language:English

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Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • The aggregation of β-amyloid peptide 42 results in the formation of toxic oligomers and plaques, which plays a pivotal role in Alzheimer's disease pathogenesis. Aβ42 is one of several Aβ peptides, all of Aβ30 to Aβ43 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 Aβ42-lowering anti-amyloidogenic compounds for the treatment of AD. Gamma-secretase modulators change the relative proportion of secreted Aβ 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 Aβ-like peptides, but that only the production of Aβ-like proteins from EphA4 is modulated by GSMs, but with an order of magnitude lower potency as compared to Aβ modulation. Collectively, these results suggest that GSMs are selective for γ-secretase-mediated Aβ production.

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  • Lundkvist, Johan (author)
  • Wanngren, JohannaKarolinska Institutet (author)
  • Kvartsberg, Hlin,1987Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xjohhl (author)
  • Jin, ShaoBoKarolinska Institutet (author)
  • Larssen, Pia (author)
  • Wu, Dan (author)
  • Oliveira, Daniel VKarolinska Institutet (author)
  • Minta, KarolinaGothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xminka (author)
  • Brinkmalm, GunnarGothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xbrigu (author)
  • Zetterberg, Henrik,1973Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xzethe (author)
  • Blennow, Kaj,1958Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xbleka (author)
  • Nordvall, GunnarKarolinska Institutet (author)
  • Winblad, BengtKarolinska Institutet (author)
  • Portelius, Erik,1977Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xporer (author)
  • Karlström, HelenaKarolinska Institutet (author)
  • Karolinska InstitutetInstitutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi (creator_code:org_t)

Related titles

  • In:Journal of cellular and molecular medicine: Wiley26:3, s. 880-8921582-49341582-1838

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