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The effect of APOE genotype on astrocytic phenotypes in sporadic Alzheimer’s disease

Pryce-Roberts, Adele 2020. The effect of APOE genotype on astrocytic phenotypes in sporadic Alzheimer’s disease. PhD Thesis, Cardiff University.
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Alzheimer’s disease is the most common form of dementia worldwide accounting for between 60 and 70% of cases. For many years, Alzheimer’s disease has been considered a disease driven by beta-amyloid, however this has been increasingly questioned, largely due to the poor correlation between amyloid deposition and the cognitive deficits seen in the disease plus the failure of a multitude of anti-amyloid drugs. A better understanding of the pathogenesis of the disease, especially the first cellular events, is vital in the development of disease modifying treatments that could address this global health issue. The best neuropathological correlate of the cognitive deficits seen in Alzheimer’s disease is synaptic loss and the most significant genetic risk factor is variation of the Apoliprotein E (APOE) protein sequence, particularly the APOE3 and APOE4 alleles. The objective of this thesis was to use CRISPR-Cas9 technology to create isogenic APOE cell lines differing by only their APOE 3 and 4 genotypes. As ApoE is largely produced by astrocytes within the central nervous system, the effects of these genetic variations on astrocyte cell biology was investigated, in particular effects on ApoE expression, glutamate uptake, phagocytosis, cholesterol homeostasis and the expression profile of pro-inflammatory cytokines. All of these characteristics were changed in cells carrying the E4 genotype. I describe how these may be connected by a common pathway and outline future directions for further development of the cell model. Overall, this thesis describes a model system which has elucidated a number of astrocytic phenotypes associated with the APOE genotype highlighting areas of enquiry that are most likely to be fruitful

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 21 April 2021
Last Modified: 21 Apr 2021 06:46

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