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Investigating the role of microglia risk genes in Alzheimer’s disease

Vassileva, Marieta 2023. Investigating the role of microglia risk genes in Alzheimer’s disease. PhD Thesis, Cardiff University.
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Alzheimer’s disease (AD) is the most common form of dementia. It affects over 155 million people worldwide and represents a huge social and economic burden. Recent genetic advances have revealed that microglia play a key role in disease development and understanding how different microglia genes contribute to disease is crucial for future treatment development. A single nucleotide polymorphism within paired immunoglobulin-like receptor alpha (PILRa) was identified to be protective against AD. The G78R variant alters the conformation of the receptor ligand binding pocket and reduces receptor activation. The function of the G78R variant was investigated through developing and validating novel microglia relevant in vitro models. Using functional approaches, the data suggests that PILRa might be involved in regulating crucial microglia functions such as cytokine release. In addition, utilising human relevant iPS derived microglia lines a brain relevant ligand of PILRa, PANP was functionally explored. Another important gene for microglia function is the spleen tyrosine kinase (SYK) which can modulate the response of multiple core microglia pathways and is positioned downstream of important risk gene targets. Utilising a conditional knock-out (cKO) model of Syk in the APPNL-G-F mouse model of AD the role of the gene in microglia was investigated. Some novel transcriptomic data identifies the initial cell response upon Syk deletion including metabolic changes and pathways linked to mitochondrial function. Additionally, investigating the response during disease progression in aged animals, identifies that Syk is involved in regulating microglia DAM transcriptomic signature. This is paired with pronounced morphological changes, including reduced number of microglia cells and diminished response to the presence of plaques. The genes of interest in this thesis represent an important part of microglia activation and inhibition and demonstrate why it is important to understand microglia responses in more detail to develop better treatments.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 23 January 2024
Last Modified: 23 Jan 2024 16:32

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