Phillips, AEM; (2018) TREM2 and Complement in Microglia; Implications for Neurodegeneration. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Microglial responses critically underpin pathological processes associated with progressive neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease. Regulated inflammation is essential in the healthy brain for the removal of debris and apoptotic cells. However, prolonged inflammation, often attributed to dysregulated microglial activation, is neurotoxic and implicated in the pathogenesis of multiple neurodegenerative diseases. GWAS have identified mutations in the genes for triggering receptor expressed on myeloid cells (TREM2) and Complement Receptor 1 (CR1) as putative risk factors for late-onset Alzheimer’s disease (LOAD) (Guerreiro et al. 2013a; Jonsson et al. 2013; Lambert et al. 2013).TREM2 is a major microglia-specific gene and may act as a lock to repress microglial pro-inflammatory activity, whilst promoting protective responses such as chemotaxis and phagocytosis. CR1 is a member of the regulators of the complement activation family and is reported to be expressed on rodent microglia, although there is a lack of clear evidence of human microglial expression. CR1 acts to clear opsonised immune complexes from the blood as well as acting as a complement activation regulator. CRISPR/Cas9-generated TREM2 knockdown and knockout mouse microglia cell lines have been characterised and utilised for functional experiments in order to further appreciate the role of TREM2 in microglia, alongside iPSC-derived microglia-like cells (iPSC-MGLC) generated from patients carrying TREM2 mutations linked to AD and Nasu Hakola Disease. TREM2 knockout lines have altered actin structures and demonstrate defective responses to stimuli compared with WT cells. Both TREM2 knockout cell lines and human iPSC-MGLC display altered cytokine responses and phagocytosis compared to control cells. Human tissues, including AD brain samples and blood derived cells, have been used to confirm a lack of CR1 in unstimulated human microglia and iPSC-MGLC were utilised to investigate the effect of TREM2 mutations on the expression of other AD-linked complement factors, including C1q and CR3.

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