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γ-Secretase modulat...
γ-Secretase modulators show selectivity for γ-secretase-mediated amyloid precursor protein intramembrane processing.
- Article/chapterEnglish2022
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LIBRIS-ID:oai:gup.ub.gu.se/312046
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https://gup.ub.gu.se/publication/312046URI
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https://doi.org/10.1111/jcmm.17146DOI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:148380416URI
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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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)
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Wanngren, JohannaKarolinska Institutet
(author)
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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)
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Jin, ShaoBoKarolinska Institutet
(author)
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Larssen, Pia
(author)
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Wu, Dan
(author)
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Oliveira, Daniel VKarolinska Institutet
(author)
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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)
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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)
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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)
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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)
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Nordvall, GunnarKarolinska Institutet
(author)
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Winblad, BengtKarolinska Institutet
(author)
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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)
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Karlström, HelenaKarolinska Institutet
(author)
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Karolinska InstitutetInstitutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
(creator_code:org_t)
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In:Journal of cellular and molecular medicine: Wiley26:3, s. 880-8921582-49341582-1838
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Weber, Tobias A
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Lundkvist, Johan
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Wanngren, Johann ...
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Kvartsberg, Hlin ...
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Jin, ShaoBo
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Larssen, Pia
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Wu, Dan
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Oliveira, Daniel ...
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Minta, Karolina
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Brinkmalm, Gunna ...
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Zetterberg, Henr ...
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Blennow, Kaj, 19 ...
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Nordvall, Gunnar
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Winblad, Bengt
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University of Gothenburg
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