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The generation of antibodies as tools to characterise triggering receptor expressed on Myeloid Cells 2 (TREM2) and explore its role in Alzheimer’s Disease

Fathalla, Dina 2021. The generation of antibodies as tools to characterise triggering receptor expressed on Myeloid Cells 2 (TREM2) and explore its role in Alzheimer’s Disease. PhD Thesis, Cardiff University.
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Abstract

Alzheimer’s disease (AD) is the most common form of dementia, accounting for 60-70% of cases. Genome-wide association and genetic meta-analysis studies have identified several risk genes linked with late onset AD, a major one being triggering receptor expressed on myeloid cells 2 (TREM2). Variants of TREM2 have been associated with partial loss of function, such as impaired ligand binding and reduced microglial inflammatory responses, and recent studies have demonstrated a key role for TREM2 in microglial modulation in the healthy brain and in AD. However, conflicting results in the literature indicate that the role of TREM2 is more complex than once thought, and a better understanding of the functions and relevance of TREM2, and its soluble counterpart, is necessary to further the knowledge of AD pathogenesis and identify potential therapeutic targets. There is currently a lack of reliable commercial anti-TREM2 antibodies that can detect and modulate TREM2 in human and animal systems. This thesis describes the production and characterisation of a panel of monoclonal and polyclonal antibodies raised against human and mouse TREM2. Of these antibodies, a complementary pair was selected and optimised for the establishment of an in-house ELISA for the detection of soluble TREM2 in human samples. This assay was used to analyse a cohort of AD and mild cognitive impairment (MCI) patients alongside age-matched controls, where sTREM2 levels were found to positively correlate with age, but not clinical status. Novel antibodies were also generated against peptides representing the two most common TREM2 variants associated with increased susceptibility to AD; R47H and R62H. Overall, this thesis discusses the characterisation and application of the generated anti-TREM2 antibodies and demonstrates their future potential for use in functional assays.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 26 March 2021
Last Modified: 25 Jun 2021 14:34
URI: http://orca.cardiff.ac.uk/id/eprint/140108

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