Uras, Giuseppe;
Li, Xinuo;
Manca, Alessia;
Pantaleo, Antonella;
Bo, Marco;
Xu, Jinyi;
Allen, Stephanie;
(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.
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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.
| Type: | Article |
|---|---|
| Title: | Development of p-Tau Differentiated Cell Model of Alzheimer’s Disease to Screen Novel Acetylcholinesterase Inhibitors |
| Location: | Switzerland |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3390/ijms232314794 |
| Publisher version: | https://doi.org/10.3390/ijms232314794 |
| Language: | English |
| Additional information: | 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/). |
| Keywords: | Alzheimer; AChE; GSK3-β; inhibitors; Tau; hyperphosphorylation |
| 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 > Clinical and Movement Neurosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10184217 |
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