Cannavo, Claudia;
(2021)
APP cellular biology in a mouse model of Down syndrome.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Down syndrome (DS) is a genetic condition caused by trisomy of human chromosome 21 (Hsa21). Among other characteristics, DS causes an increased risk of developing an early form of Alzheimer’s disease (AD). In Alzheimer’s disease in Down syndrome (AD-DS), trisomy of the Hsa21 amyloid precursor protein gene (APP) is sufficient and necessary to cause AD. My study aims to clarify the link between Hsa21 trisomy and early AD pathology with a focus on APP cellular biology. I used the Dp1Tyb mouse model of DS with a segmental duplication of 148 mouse genes homologous to Hsa21. In addition, I made a mouse model with trisomy of 147 genes homologous to Hsa21 but only two copies of App (Dp1Tyb/App+/-) to study the role of App copy number. First, I quantified volume and number of early endosomes, one of the main sites of APP cleavage and known to be altered in AD and AD-DS, in mouse embryonic fibroblasts (MEFs). Secondly, I assessed APP processing, APP degradation rate and APP dosage sensitivity in MEFs. None of these phenotypes were altered in Dp1Tyb MEFs compared to Dp1Tyb/App+/- and WT littermates. I then investigated dosage sensitivity of APP and some of its cleavage products, amyloid β (Aβ) accumulation, and proteostasis regulation in the mouse cortex and hippocampus at 3 and 6 months of age. APP and APP derived C-terminals (CTFs) were consistently dosage sensitive across both areas and ages, while Aβ production and proteostasis regulation changed depending on the time point or tissue analysed. Overall my study highlighted the importance of APP overexpression for the development of AD-DS-related early cellular phenotypes, but also suggested that other genetic factors regulate these changes. Future studies could follow on from these findings to map the observed phenotypes to precise time points and to a smaller section of Hsa21 homologous genes.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | APP cellular biology in a mouse model of Down syndrome |
| Event: | UCL (University College London) |
| 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 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 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 Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10125885 |
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