Jones, Megan Elizabeth Easby;
(2022)
A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during ageing and in Alzheimer’s disease.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Synapse loss strongly correlates with memory impairment in Alzheimer’s disease (AD). However, the underlying mechanisms are poorly understood. Deficient Wnt signalling, a pathway required for synapse integrity in the mature brain, contributes to synapse degeneration in AD. A variant of LRP6 (LRP6-Val), which has a single amino acid substitution of isoleucine to valine in the fourth extracellular β-propeller domain, reduces Wnt signalling and is linked to late-onset AD. However, the impact of LRP6-Val on synapses in the ageing brain and AD has not been addressed. Our lab generated a novel knock-in mouse model carrying the Lrp6-val variant. My analyses of these mice revealed an age-dependent decrease in excitatory synapse number and a concomitant increase in inhibitory synapse number. Furthermore, microglia number is elevated in aged Lrp6-val mice. Examination of the mechanism by which Lrp6-val induces synaptic defects revealed that neurons from Lrp6-val mice do not respond to Wnt7a to promote synapse formation. Finally, to investigate the impact of Lrp6-val in AD, Lrp6-val mice were crossed to the NL-G-F AD model. Lrp6-val does not affect Aβ levels or plaque load. However, synapse loss is exacerbated around the plaques. My novel results uncover a role for the Lrp6-val variant in the ageing and AD brain. I demonstrate that Lrp6-val reduces the number of excitatory synapses and increases inhibitory synapse number with age and enhances synapse vulnerability in AD. Moreover, these findings demonstrate that a single amino acid substitution in the fourth extracellular β-propeller domain impairs the ability of Wnt7a to promote synapse formation, suggesting that Wnt7a could interact with this region. Thus, my work reveals the function of a variant of Lrp6 associated with AD in synapse degeneration in ageing and AD.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during ageing and in Alzheimer’s disease |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) Licence (https://creativecommons.org/licenses/by-nc-nd/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 > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10157298 |
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