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Unravelling the molecular basis of the association of genetic variation in the clusterin gene with risk of Alzheimer’s disease

Veteleanu, Ioana-Aurora 2023. Unravelling the molecular basis of the association of genetic variation in the clusterin gene with risk of Alzheimer’s disease. PhD Thesis, Cardiff University.
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Background: Genome-wide association studies (GWAS) identified clusterin (CLU) as the third most significant genetic risk factor for Alzheimer’s disease (AD), while biomarker studies found clusterin to be significantly elevated in AD. The work in this thesis aimed to address the incompletely understood association between intronic SNPs in CLU and risk for AD through relating genotypes at CLU single nucleotide polymorphisms (SNPs) to plasma clusterin levels and measuring secreted and intracellular clusterin in induced pluripotent stem cell (iPSC)-derived astrocytes. Methods: To quantify clusterin levels in human biofluids, a panel of monoclonal antibodies was generated through hybridoma technology. A sandwich ELISA was developed and characterised, and clusterin was measured in plasma and CSF from subjects with AD and healthy individuals. To study the effects of SNPs in CLU on clusterin synthesis, five iPSC lines carrying different genotypes at genome-wide significant (GWS) SNPs were differentiated into astrocytes, and intracellular and secreted clusterin was measured at mRNA and protein levels. Results: Monoclonal antibodies specifically bound human clusterin in serum and a sensitive ELISA was set up (Chapter 2). Clusterin was significantly elevated in plasma from subjects with AD or Down Syndrome compared to healthy controls, and no significant change was observed in CSF (Chapter 3). Using an endophenotype-GWAS approach, no SNPs were found to be significantly associated with changes in plasma clusterin protein levels (Chapter 4). In iPSC-derived astrocytes, intracellular clusterin was significantly elevated at the gene and protein level in rs11136000 C/C carriers (Chapter 5). Conclusions: Increased clusterin levels in AD compared to control were not influenced by CLU GWS SNPs, and may reflect other aspects of AD pathology observed in the periphery. However, these SNPs might have functional effects particularly in the brain, as intracellular clusterin isoforms from astrocytes were found to be significantly elevated in carriers of risk alleles. This work provides insight into the mechanistic role of SNPs in CLU in modulating AD risk by altering clusterin secretion.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 13 May 2024
Last Modified: 13 May 2024 16:23

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