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, Bergström P, Portelius E, Zetterberg H

Molecular and Cellular Neuroscience 85 (-) 211-219 [2017-12-00; online 2017-11-08]

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.

Integrated Microscopy Technologies Gothenburg [Service]

PubMed 29104140

DOI 10.1016/j.mcn.2017.10.009

Crossref 10.1016/j.mcn.2017.10.009

pii: S1044-7431(16)30246-9