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Low-dose γ-secretas...
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Agholme, LottaGothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
(author)
Low-dose γ-secretase inhibition increases secretion of Aβ peptides and intracellular oligomeric Aβ.
- Article/chapterEnglish2017
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LIBRIS-ID:oai:gup.ub.gu.se/260629
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https://gup.ub.gu.se/publication/260629URI
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https://doi.org/10.1016/j.mcn.2017.10.009DOI
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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γ-Secretase inhibitors have been considered promising drug candidates against Alzheimer's disease (AD) due to their ability to reduce amyloid-β (Aβ) production. However, clinical trials have been halted due to lack of clinical efficacy and/or side effects. Recent in vitro studies suggest that low doses of γ-secretase inhibitors may instead increase Aβ production. Using a stem cell-derived human model of cortical neurons and low doses of the γ-secretase inhibitor DAPT, the effects on a variety of Aβ peptides were studied using mass spectrometry. One major focus was to develop a novel method for specific detection of oligomeric Aβ (oAβ), and this was used to study the effects of low-dose γ-secretase inhibitor treatment on intracellular oAβ accumulation. Low-dose treatment (2 and 20nM) with DAPT increased the secretion of several Aβ peptides, especially Aβx-42. Furthermore, using the novel method for oAβ detection, we found that 2nM DAPT treatment of cortical neurons resulted in increased oAβ accumulation. Thus, low dose-treatment with DAPT causes both increased production of long, aggregation-prone Aβ peptides and accumulation of intracellular Aβ oligomers, both believed to contribute to AD pathology.
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Clarin, MarcusGothenburg 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)xclmar
(author)
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Gkanatsiou, EleniGothenburg 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)xgkael
(author)
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Kettunen, PetronellaGothenburg 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)xketpe
(author)
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Chebli, JasmineGothenburg 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)xcheja
(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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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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Bergström, PetraGothenburg 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)xbpeta
(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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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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Göteborgs universitetInstitutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
(creator_code:org_t)
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In:Molecular and cellular neurosciences: Elsevier BV85, s. 211-2191095-93271044-7431
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Agholme, Lotta
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Clarin, Marcus
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Gkanatsiou, Elen ...
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Kettunen, Petron ...
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Chebli, Jasmine
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Brinkmalm, Gunna ...
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