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Low-dose γ-secretase inhibition increases secretion of Aβ peptides and intracellular oligomeric Aβ.

Artikel i vetenskaplig tidskrift
Författare Lotta Agholme
Marcus Clarin
Eleni Gkanatsiou
Petronella Kettunen
Jasmine Chebli
Gunnar Brinkmalm
Kaj Blennow
Petra Bergström
Erik Portelius
Henrik Zetterberg
Publicerad i Molecular and cellular neurosciences
Volym 85
Sidor 211-219
ISSN 1095-9327
Publiceringsår 2017
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
Sidor 211-219
Språk en
Länkar dx.doi.org/10.1016/j.mcn.2017.10.00...
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Neurovetenskaper, Neurovetenskap, Neurobiologi

Sammanfattning

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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