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Investigating how Alzheimer's Disease risk genes Spi1 and Abi3 modulate Macrophage physiology

Jones, Ruth Elizabeth 2019. Investigating how Alzheimer's Disease risk genes Spi1 and Abi3 modulate Macrophage physiology. PhD Thesis, Cardiff University.
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Patients with Alzheimer’s Disease (AD) represent over 60 % of all dementia cases and current treatments cannot slow disease progression. Multiple AD-risk genes suggest microglia contribute to AD pathophysiology. This thesis investigates two AD-risk genes, SPI1 and ABI3. SPI1 encodes the transcription factor PU.1, essential in myeloid populations. SPI1/PU.1 is thought to affect AD-risk gene expression and an earlier AD-onset is predicted in individuals with high SPI1-expression polymorphism. Current literature suggests increased SPI1/PU.1 expression alters the transcriptome of microglia and increases AD risk. PU.1 is essential for the survival of macrophages (MØ) raising concerns that treatment reducing PU.1 may affect peripheral MØ in the immunocompromised elderly. This thesis confirmed low PU.1 expression reduced microglial phagocytic capacity. RNA-Sequencing analysis identified over 162 microglia genes controlled by the amount of PU.1 expressed. Some genes were only detected in a Spi1 over-expression dataset. 21 genes with significant expression-alterations showed an enriched signal for the IGAP (human AD-risk) dataset. Increased microglial Spi1 expression did result in increased expression of several AD-risk genes. Microglia Spi1 RNA-Seq datasets may provide a ‘map’ for future work to investigate how Spi1 affects microglia function. ABI3 is thought to inhibit actin-cytoskeleton reorganisation impacting several MØ functions. Newly developed Abi3 KO mice were used to investigate the function of Abi3 in pMØ and in cell lines derived from these mice. Abi3 appeared to be expressed by a subset of peritoneal MØ (pMØ) and Abi3 KO pMØ had a moderately-reduced phagocytic capacity ex vivo. In vitro work suggested that M-CSF induced cell morphology changes are also subtly changed in cells lacking Abi3. Therefore, Abi3 KO did appear to modify the function of the actin cytoskeleton in MØs. Overall, this thesis demonstrated the AD-risk genes SPI1 and ABI3 can impact microglia/MØ physiology and provides some insights into how these changes might contribute to AD pathology.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 12 September 2019
Last Modified: 05 Jan 2024 06:16

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