Villegas Llerena, Claudio N.;
(2019)
Full genome analysis of microglial activation; ramifications of TREM2.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Neuroinflammation is a pathological hallmark of Alzheimer's disease (AD) and it is well established that microglia, the brain's resident phagocytes, are pivotal for the immune response observed in AD. In the healthy brain, microglia attack and remove pathogens and cell debris, but have been shown to become reactive in AD. An apparent link between microglia and AD is Amyloid β (Aβ), which accumulates in the plaques observed in the brains of AD patients and has been reported as a microglia activator. Genome Wide Association Studies (GWAS) have allowed the identification of more than 20 genetic risk associations to AD. Many of these associations highlight the importance of immune pathways (and others) in AD. More recently, the identification of mutations in TREM2 (Triggering Receptor Expressed on Myeloid Cells 2), a gene exclusively expressed by microglia in the brain, has brought microglial activation and dysfunction back to the attention of the AD community. The main focus of this study is to understand microglial activation elicited by different stimuli including Aβ1-42 monomers, oligomers and fibrils- with regards to their inflammatory activation status (M1, M2 or other) and whole-genome expression profile. To this end, the mouse-derived BV2 cell line was used to assess gene expression changes during microglial activation. Data shows that M1 and M2 activators alter gene expression of AD-associated genes in a manner that is potentially detrimental for AD progression. A second objective of this thesis was to use the CRISPR/Cas9 gene editing technology for the generation of Trem2-deficient BV2 cell lines. As a result, Trem2 +/- (haploinsufficient) and Trem2 -/- (knockout) BV2 cell lines were generated. Subsequently, these cell lines were characterised in terms of their phagocytic, proliferation, migration, cytokine release capacities and whole genome expression. In consequence, this study provides new and wellcharacterised in vitro models for the study of Trem2 function.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Full genome analysis of microglial activation; ramifications of TREM2 |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/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 Brain Sciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10075140 |
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