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

Journal article
Authors Lotta Agholme
Marcus Clarin
Eleni Gkanatsiou
Petronella Kettunen
Jasmine Chebli
Gunnar Brinkmalm
Kaj Blennow
Petra Bergström
Erik Portelius
Henrik Zetterberg
Published in Molecular and cellular neurosciences
Volume 85
Pages 211-219
ISSN 1095-9327
Publication year 2017
Published at Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Pages 211-219
Language en
Links dx.doi.org/10.1016/j.mcn.2017.10.00...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Neurosciences, Neuroscience, Neurobiology

Abstract

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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