eprintid: 10065950
rev_number: 16
eprint_status: archive
userid: 608
dir: disk0/10/06/59/50
datestamp: 2019-01-16 10:16:33
lastmod: 2021-09-26 23:09:32
status_changed: 2019-01-16 10:16:33
type: article
metadata_visibility: show
creators_name: Sogorb-Esteve, A
creators_name: Garcia-Ayllon, M-S
creators_name: Llansola, M
creators_name: Felipo, V
creators_name: Blennow, K
creators_name: Saez-Valero, J
title: Inhibition of gamma-Secretase Leads to an Increase in Presenilin-1
ispublished: pub
divisions: UCL
divisions: B02
divisions: C07
divisions: D07
divisions: F86
keywords: Alzheimer’s disease, Presenilin-1, γ-Secretase inhibitor, Therapy
note: © The Author(s) 2017.
Open Access:
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
abstract: γ-Secretase inhibitors (GSIs) are potential therapeutic agents for Alzheimer’s disease (AD); however, trials have proven disappointing. We addressed the possibility that γ-secretase inhibition can provoke a rebound effect, elevating the levels of the catalytic γ-secretase subunit, presenilin-1 (PS1). Acute treatment of SH-SY5Y cells with the GSI LY-374973 (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, DAPT) augments PS1, in parallel with increases in other γ-secretase subunits nicastrin, presenilin enhancer 2, and anterior pharynx-defective 1, yet with no increase in messenger RNA expression. Over-expression of the C-terminal fragment (CTF) of APP, C99, also triggered an increase in PS1. Similar increases in PS1 were evident in primary neurons treated repeatedly (4 days) with DAPT or with the GSI BMS-708163 (avagacestat). Likewise, rats examined after 21 days administered with avagacestat (40 mg/kg/day) had more brain PS1. Sustained γ-secretase inhibition did not exert a long-term effect on PS1 activity, evident through the decrease in CTFs of APP and ApoER2. Prolonged avagacestat treatment of rats produced a subtle impairment in anxiety-like behavior. The rebound increase in PS1 in response to GSIs must be taken into consideration for future drug development.
date: 2018-06
date_type: published
publisher: SPRINGER
official_url: https://doi.org/10.1007/s12035-017-0705-1
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
article_type_text: Article
verified: verified_manual
elements_id: 1601032
doi: 10.1007/s12035-017-0705-1
language_elements: English
lyricists_name: Sogorb Esteve, Aitana
lyricists_id: AASOG25
actors_name: Cuccu, Clara
actors_id: CCCUC40
actors_role: owner
full_text_status: public
publication: Molecular Neurobiology
volume: 55
number: 6
pagerange: 5047-5058
pages: 12
issn: 1559-1182
citation:        Sogorb-Esteve, A;    Garcia-Ayllon, M-S;    Llansola, M;    Felipo, V;    Blennow, K;    Saez-Valero, J;      (2018)    Inhibition of gamma-Secretase Leads to an Increase in Presenilin-1.                   Molecular Neurobiology , 55  (6)   pp. 5047-5058.    10.1007/s12035-017-0705-1 <https://doi.org/10.1007/s12035-017-0705-1>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10065950/1/Sogorb-Esteve2018_Article_InhibitionOf%CE%93-SecretaseLeadsTo.pdf