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γ-Secretase modulat...
γ-Secretase modulators show selectivity for γ-secretase-mediated amyloid precursor protein intramembrane processing.
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Weber, Tobias A (author)
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- Lundkvist, Johan (author)
- Karolinska Institutet
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- Wanngren, Johanna (author)
- Karolinska Institutet
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- Kvartsberg, Hlin, 1987 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Jin, ShaoBo (author)
- Karolinska Institutet
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Larssen, Pia (author)
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Wu, Dan (author)
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- Oliveira, Daniel V (author)
- Karolinska Institutet
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- Minta, Karolina (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Brinkmalm, Gunnar (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Zetterberg, Henrik, 1973 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Blennow, Kaj, 1958 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Nordvall, Gunnar (author)
- Karolinska Institutet
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- Winblad, Bengt (author)
- Karolinska Institutet
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- Portelius, Erik, 1977 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Karlström, Helena (author)
- Karolinska Institutet
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(creator_code:org_t)
- 2021-12-20
- 2022
- English.
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In: Journal of cellular and molecular medicine. - : Wiley. - 1582-4934 .- 1582-1838. ; 26:3, s. 880-892
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Abstract
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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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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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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show more...
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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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Portelius, Erik, ...
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Karlström, Helen ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Journal of cellu ...
- By the university
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University of Gothenburg
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Karolinska Institutet