eprintid: 10184217
rev_number: 7
eprint_status: archive
userid: 699
dir: disk0/10/18/42/17
datestamp: 2023-12-20 09:44:06
lastmod: 2023-12-20 09:44:06
status_changed: 2023-12-20 09:44:06
type: article
metadata_visibility: show
sword_depositor: 699
creators_name: Uras, Giuseppe
creators_name: Li, Xinuo
creators_name: Manca, Alessia
creators_name: Pantaleo, Antonella
creators_name: Bo, Marco
creators_name: Xu, Jinyi
creators_name: Allen, Stephanie
creators_name: Zhu, Zheying
title: Development of p-Tau Differentiated Cell Model of Alzheimer’s Disease to Screen Novel Acetylcholinesterase Inhibitors
ispublished: pub
divisions: UCL
divisions: B02
divisions: C07
divisions: D07
divisions: F84
keywords: Alzheimer; AChE; GSK3-β; inhibitors; Tau; hyperphosphorylation
note: Copyright © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
abstract: Alzheimer’s disease (AD) is characterized by an initial accumulation of amyloid plaques and neurofibrillary tangles, along with the depletion of cholinergic markers. The currently available therapies for AD do not present any disease-modifying effects, with the available in vitro platforms to study either AD drug candidates or basic biology not fully recapitulating the main features of the disease or being extremely costly, such as iPSC-derived neurons. In the present work, we developed and validated a novel cell-based AD model featuring Tau hyperphosphorylation and degenerative neuronal morphology. Using the model, we evaluated the efficacy of three different groups of newly synthesized acetylcholinesterase (AChE) inhibitors, along with a new dual acetylcholinesterase/glycogen synthase kinase 3 inhibitor, as potential AD treatment on differentiated SH-SY5Y cells treated with glyceraldehyde to induce Tau hyperphosphorylation, and subsequently neurite degeneration and cell death. Testing of such compounds on the newly developed model revealed an overall improvement of the induced defects by inhibition of AChE alone, showing a reduction of S396 aberrant phosphorylation along with a moderate amelioration of the neuron-like morphology. Finally, simultaneous AChE/GSK3 inhibition further enhanced the limited effects observed by AChE inhibition alone, resulting in an improvement of all the key parameters, such as cell viability, morphology, and Tau abnormal phosphorylation.
date: 2022-12-01
date_type: published
publisher: MDPI
official_url: https://doi.org/10.3390/ijms232314794
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1995999
doi: 10.3390/ijms232314794
medium: Electronic
pii: ijms232314794
lyricists_name: Uras, Giuseppe
lyricists_id: GURAS33
actors_name: Flynn, Bernadette
actors_id: BFFLY94
actors_role: owner
funding_acknowledgements: [School of Pharmacy, The University of Nottingham, UK]; [China Scholarship Council, China]; [Erasmus+ programme, Italy]
full_text_status: public
publication: International Journal of Molecular Sciences
volume: 23
number: 23
article_number: 14794
pages: 18
event_location: Switzerland
issn: 1661-6596
citation:        Uras, Giuseppe;    Li, Xinuo;    Manca, Alessia;    Pantaleo, Antonella;    Bo, Marco;    Xu, Jinyi;    Allen, Stephanie;           Uras, Giuseppe;  Li, Xinuo;  Manca, Alessia;  Pantaleo, Antonella;  Bo, Marco;  Xu, Jinyi;  Allen, Stephanie;  Zhu, Zheying;   - view fewer <#>    (2022)    Development of p-Tau Differentiated Cell Model of Alzheimer’s Disease to Screen Novel Acetylcholinesterase Inhibitors.                   International Journal of Molecular Sciences , 23  (23)    , Article 14794.  10.3390/ijms232314794 <https://doi.org/10.3390/ijms232314794>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10184217/1/ijms-23-14794.pdf