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Title: Molecular and cellular investigation of Alzheimer's disease associated risk loci : BIN1 and CD2AP
Author: Barrett, Anna
ISNI:       0000 0004 7223 4826
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2017
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Genome wide association studies have identified genes associated with Late Onset Alzheimer’s disease (AD). Pathway analyses have used this data to implicate a number of biological mechanisms in AD pathogenesis. Endocytosis has been implicated in AD and is a critical biological mechanism involved in the production of Aβ. BIN1 and CD2AP are associated with AD and function in endocytosis. This thesis describes how depletion of BIN1 and CD2AP has contradicting effects on the processing of APP in a human brain cell line and affects endocytosis in different ways, suggesting multiple cellular trafficking mechanisms may be involved in Aβ production. As most genetic variants associated with complex diseases are located in the non-coding region of the genome, they may contribute to disease susceptibility by disrupting gene regulation. Variants at the BIN1 locus associated with AD are located approximately 30 Kb from the coding region, suggesting BIN1 regulation may be a risk mechanism in AD. BIN1 expression is influenced by cis-regulatory mechanisms in prefrontal cortex tissue. Differential allele expression implied that this cis-regulation was influenced by DNA variants. The variant responsible was not identified but there was suggestive evidence for an intronic variant associated with AD. ChIP-Seq and DNase-Seq data identified chromatin modifications and transcription factor binding in immune cell types at the BIN1 risk locus. Gene reporter assays showed that the BIN1 locus was capable of functioning as a genetic enhancer. Furthermore, assays used to investigate DNA protein interactions showed that SPI1, an AD associated transcription factor with a critical immune function, bound to the BIN1 locus. The BIN1 index SNP had no effect on gene expression or protein binding, but may have a greater impact on additional disease relevant immune cell types. Finally, gene-editing techniques were explored as a mechanism for generating isogenic cell models to investigate the effect of AD associated variants.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available