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Dysregulation of canonical Wnt signalling in mutant App knock-in Alzheimer's disease models

Liu, Tiansheng; (2023) Dysregulation of canonical Wnt signalling in mutant App knock-in Alzheimer's disease models. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Alzheimer’s disease (AD) characterised by a decline in cognitive ability is the most common type of dementia. Dysregulation of Wnt signalling has been shown to play an important role in synaptic dysfunction and amyloidosis, contributing to the development of AD. Although studies have shown alterations of Wnt signalling components in transgenic (Tg) mouse models overexpressing mutant APP, more detailed investigations of underlying molecular signalling pathway dysfunction are required in AD models representing disease progression in human patients more accurately. In this study, canonical Wnt signalling was investigated in App NL-F knock-in mouse models. Aβ deposition was confirmed in App NL-F mouse brains which started from 6-month-old. mRNA expressions of Axin2 and Dvl1 showed decreases in 3-month-old App NL-F mice versus wildtypes. Protein levels of canonical Wnt signalling components, including pLRP6, β-catenin, and BDNF decreased initially in 3-month-old App NL-F mouse brains versus wildtypes when Aβ plaques are not detectable. Also, more significant reductions of these proteins and marked alterations of other Wnt components were found in 12-month-old App NL-F mouse brains versus age-matched wildtypes. Interestingly, aged female App NL-F mice showed more significant downregulation effects on canonical Wnt signalling components versus wildtypes compared to the changes in male mice. The downregulation of the canonical Wnt signalling pathway was further confirmed in primary cortical cultures. In addition, decreased density of dendritic spines, vGluT1, and PSD95 were found in App NL-F cortical neurons. Wnt activity stimulation with the Wnt3a ligand reversed this synaptic impairment while Wnt inhibition with Dkk1 and XAV939 exacerbated the effect. Taken together, these findings suggest that App NL-F mutants downregulate canonical Wnt signalling early in vivo showing sex differences in aged mice. Also, canonical Wnt signalling regulates App NL-F mediated synaptic dysfunction.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Dysregulation of canonical Wnt signalling in mutant App knock-in Alzheimer's disease models
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2022. 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
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 > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10164471
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