Mumford, Paige Soleil;
(2024)
Preclinical modelling of altered
neuroinflammation and interferon hyper-sensitivity in Alzheimer’s disease-Down syndrome.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and leads to a significantly elevated risk of developing early-onset Alzheimer's disease (AD). Individuals with DS have over-activated interferon signalling in the peripheral immune system, likely due to four Hsa21 genes that encode interferon receptors. The interferon pathway is activated in response to amyloid-β pathology in AD. In my study, I used mouse models to investigate how three copies of the Hsa21 interferon receptor genes altered interferon signalling and how this interacted with the response to amyloid pathology. The Dp1Tyb mouse model has three-copies of ~145 Hsa21 orthologous genes, including the four interferon receptor genes. The Dp2Tyb mouse model has a subregion of ~32 of those Hsa21 orthologous genes in three-copies, including the four interferon receptor genes. I characterised hippocampal microglia, proinflammatory cytokines, and interferon signalling in the Dp1Tyb and Dp2Tyb mice at baseline and found some evidence of activated interferon signalling in the Dp1Tyb but not the Dp2Tyb. Then, I treated Dp1Tyb and Dp2Tyb organotypic brain slice cultures with interferon-β and found that both models displayed a hyper-activated interferon response to stimulation which was more robust in the Dp1Tyb. Next, I determined when the AppNL-G-F, a mouse model of amyloid pathology, exhibited activated interferon signalling to inform my experimental design. I then crossed the AppNL-G-F with the Dp2Tyb to create the Dp2*AppNL-G-F model which has both three-copies of the Dp2Tyb region and amyloid pathology. In the model cross, three-copies of the Dp2Tyb region did not modify amyloid biology but did hyper-activate the interferon response to pathology and perturbed behaviour. Overall, my study demonstrated that interferon hyper-sensitivity can occur in the brain in DS mouse models with three-copies of the Hsa21 interferon receptor genes, and that this potentially modifies the neuroinflammatory response to amyloid pathology.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Preclinical modelling of altered neuroinflammation and interferon hyper-sensitivity in Alzheimer’s disease-Down syndrome |
| 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 > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10186874 |
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