Investigating glial roles of Alzheimer’s disease risk genes, using drosophila models

MacKinnon, Eilish 2022. Investigating glial roles of Alzheimer’s disease risk genes, using drosophila models. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Genetics plays a significant role in Alzheimer’s disease (AD) risk, with multiple genetic risk variants uncovered by Genome Wide Association Studies (GWAS), many of which are enriched in microglia, the brains resident immune cells. Microglia are responsible for central nervous system (CNS) maintenance, injury response and fighting infection. There is clear evidence microglial dysfunction plays an critical role in AD pathogenesis, suggesting therapeutically targeting these cells may be of benefit. Our understanding of how these risk genes influence glial responses throughout age is limited, and how their activity in glia contributes to disease onset and development is largely unknown. This present study sets out to investigate potential glial roles of conserved AD risk genes, using Drosophila melanogaster as a model, with the aim to elucidate novel mechanisms contributing to disease risk. A reverse candidate knockdown screen of multiple conserved AD risk genes was conducted to assess AD risk genes roles in glial mediated neurological dysfunction and longevity. Results from this screen identified novel candidate genes, including orthologs of MEF2C, NME8 and ACE that expression in glia likely contributes to a healthy ageing nervous system and survival. PLCG2 is an important candidate gene to study AD relevant functions in flies, with a coding variant (P522R) linked to reduced late onset AD (LOAD) risk. This thesis aimed to characterise the glial role of the Drosophila PLCG2 ortholog, small wing and it substrates (PI(4,5)P2 and PI(3,4,5)P3) in ageing and Aβ42 related pathology. This study characterised the utility of genetically encoded, cell type specific fluorescent reporters for measuring the PI(4,5)P2 and PI(3,4,5)P3 dynamics in the fly brain, as well as a quantifiable model of glial driven Aβ42 toxicity. Finally, transgenic Drosophila expressing human PLCG2 wildtype (P522) and AD protective (R522) variants were created to explore functional changes associated with the hypermorphic R522 variant and its contribution to reduced LOAD risk. Results highlighted a conserved role for glial sl/PLCG2 in modifying Aβ42 toxicity and confirmed a protective role of the R522 reduced risk variant compared to the common P522 variant in Aβ42 associated pathology. Taken together these results indicate modulating PLCG2 activity may be a promising therapeutic target for treatment of AD.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	16 May 2023
Last Modified:	17 May 2024 01:30
URI:	https://orca.cardiff.ac.uk/id/eprint/159550

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