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

Agholme, L; Clarin, M; Gkanatsiou, E; Kettunen, P; Chebli, J; Brinkmalm, G; Blennow, K; ... Zetterberg, H; + view all (2017) Low-dose γ-secretase inhibition increases secretion of Aβ peptides and intracellular oligomeric Aβ. Molecular and Cellular Neuroscience , 85 pp. 211-219. 10.1016/j.mcn.2017.10.009. Green open access

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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 20 nM) with DAPT increased the secretion of several Aβ peptides, especially Aβx-42. Furthermore, using the novel method for oAβ detection, we found that 2 nM 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.

Type: Article
Title: Low-dose γ-secretase inhibition increases secretion of Aβ peptides and intracellular oligomeric Aβ
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.mcn.2017.10.009
Publisher version: https://doi.org/10.1016/j.mcn.2017.10.009
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Amyloid-β, γ-secretase, DAPT, Duolink, Neurons, Oligomers
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10062187
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