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Development of p-Tau Differentiated Cell Model of Alzheimer’s Disease to Screen Novel Acetylcholinesterase Inhibitors

Uras, Giuseppe; Li, Xinuo; Manca, Alessia; Pantaleo, Antonella; Bo, Marco; Xu, Jinyi; Allen, Stephanie; Zhu, Zheying

Development of p-Tau Differentiated Cell Model of Alzheimer’s Disease to Screen Novel Acetylcholinesterase Inhibitors Thumbnail


Giuseppe Uras

Xinuo Li

Alessia Manca

Antonella Pantaleo

Marco Bo

Jinyi Xu

Stephanie Allen

Associate Professor in International Pharmacy and Traditional Medicines


Jose Luis Zugaza


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.

Journal Article Type Article
Acceptance Date Nov 16, 2022
Online Publication Date Nov 26, 2022
Publication Date Nov 26, 2022
Deposit Date Nov 28, 2022
Publicly Available Date Nov 28, 2022
Journal International Journal of Molecular Sciences
Print ISSN 1661-6596
Electronic ISSN 1422-0067
Publisher MDPI AG
Peer Reviewed Peer Reviewed
Volume 23
Issue 23
Article Number 14794
Keywords Alzheimer; AChE; GSK3-β; inhibitors; Tau; hyperphosphorylation
Public URL
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