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Exploring Alzheimer's disease and Down syndrome neuro-immune pathways using preclinical models and human post-mortem brain tissue

Farrell, Clíona; (2024) Exploring Alzheimer's disease and Down syndrome neuro-immune pathways using preclinical models and human post-mortem brain tissue. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Down syndrome (DS), caused by trisomy of chromosome 21 (Hsa21), causes the development of Alzheimer’s disease (AD), due to people with DS having three-copies of the amyloid precursor protein gene (APP). Individuals with DS have altered microglia morphology and transcriptomic signature, and increased cytokines in the brain, both before and after AD-DS development. This study aimed to understand what causes, or contributes to, these neuro-immune changes. I determined that the observed altered cytokine abundance in people who have DS recapitulates in a preclinical DS mouse model, with interleukin-1β (IL-1β) found to be elevated in the hippocampus of the Dp1Tyb mouse, which has ~145 Hsa21 orthologous genes in three-copies. IL-1β secretion occurs upon inflammasome pathway activation. I used organotypic brain slice cultures prepared from the Dp1Tyb mouse to demonstrate that raised IL-1β in DS is not occurring due to increased sensitivity to inflammasome pathway priming or activation. By measuring IL-1β abundance in mouse models of DS with subsets of Hsa21 orthologues in three-copies, I showed that the phenotype of raised IL-1β is multigenic, with more than one Hsa21 gene required in three-copies. Furthermore, I showed that this phenotype has a strong environment interaction. Using RNA sequencing, I demonstrated that the Dp1Tyb hippocampus has enrichment of neuroinflammation and interferon signalling genes, which are not altered by reducing the gene-dose of App to two-copies in the model. To further understand the similarities and differences between AD-DS, early-onset AD (EOAD), and healthy ageing in euploid individuals, I undertook a label-free proteomic study on human post-mortem brain tissue. I identified over 300 proteins that had significantly altered abundance in cases of AD-DS compared with EOAD, with most of these proteins not being encoded by Hsa21. The key AD protein, Apolipoprotein E, is significantly raised in AD-DS compared to EOAD, which correlates with APP, APP-C-terminal fragment, and microglia markers. These data highlight important differences between AD-DS and AD in the general population, which will be critical to consider when developing AD-modifying therapies for people who have DS.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Exploring Alzheimer's disease and Down syndrome neuro-immune pathways using preclinical models and human post-mortem brain tissue
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.
Keywords: Down syndrome, Neuroinflammation, Alzheimer's disease
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/10194341
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