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Development of Three-Dimensional In Vitro CNS Models to Evaluate Novel Natural Product-Derived Compounds for Alzheimer's Disease Treatment

Onuwaje, Itseoritseno (Itse); (2024) Development of Three-Dimensional In Vitro CNS Models to Evaluate Novel Natural Product-Derived Compounds for Alzheimer's Disease Treatment. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Alzheimer's disease (AD) is the leading cause of dementia, which has no current cure. A key technological challenge in developing new AD treatments is the need for preclinical testing systems capable of identifying promising treatments. Without preclinical models capable of accurately predicting drug success, pharmaceutical firms are forced to bet on expensive clinical trials (99.6% of which have failed). Researchers are increasingly looking towards 3D in vitro assays to provide more predictive preclinical testing compared to typically relied upon rodent models of AD, which often produce false positive results that do not translate to clinical success. The field is also shifting away from ‘one disease- one target- one drug’ approaches and exploring the use of multi-target therapies to treat AD. This project seeks to develop advanced 3D in vitro cell based preclinical testing systems to evaluate the therapeutic potential of a series of novel multi-target compounds for the treatment of AD. The project explored the three main components of designing a successful preclinical assay: the assay system, the assay stimulus, and the assay readout, as illustrated in Figure 0.0.1. The results indicate both human cell lines and patient derived-induced pluripotent stem cells (iPSCs) can be differentiated to generate co-cultures that serve as human-based assay systems. The results also show that disease phenotypes could be recapitulated in these systems with differing effects of disease-relevant stimuli being demonstrated across 2D and 3D co-cultures. Lastly, a unique combination of target-based and phenotypic assay read outs were applied in 2D and 3D assays in 96 and 384-well formats to evaluate the compounds and the results showed promising effects in acetylcholinesterase (AChE) inhibition and protecting against mitochondrial and oxidative stress.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Development of Three-Dimensional In Vitro CNS Models to Evaluate Novel Natural Product-Derived Compounds for Alzheimer's Disease Treatment
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL > Provost and Vice Provost Offices > VP: Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > VP: Health > Translational Research Office
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10188129
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