Insights into Apolipoprotein E: understanding the major genetic risk factor for Alzheimer’s Disease

Raulin, Ana-Caroline (2019) Insights into Apolipoprotein E: understanding the major genetic risk factor for Alzheimer’s Disease. Doctoral thesis (PhD), University of Sussex.

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Abstract

Sporadic, late-onset Alzheimer’s disease (LOAD) is the leading cause of dementia. Advanced age is the main culprit for LOAD, but the ε4 variant of APOE has been identified as a major genetic risk factor. APOE encodes Apolipoprotein E (ApoE), which exists as three isoforms. ApoE3, the most common one, confers a neutral chance for LOAD onset whereas ApoE4 presents a risk and ApoE2 is protective.
This thesis explores different avenues taken to understand the differences between the three ApoE isoforms, with the ultimate goal being to answer why and how only ApoE4 increases an individual’s susceptibility for LOAD.
In Chapter 3, the structure, stability, and propensity for aggregation for the isoforms were compared using a recombinant model of human ApoE.
In Chapter 4, I conducted a thorough exploration of both the impact of the APOE genotype on vulnerability to oxidative stress and ApoE’s differential response to oxidative stress itself, using recombinant protein and cultures from human ApoE targeted- replacement mice.
Finally, in Chapter 5, the interaction between ApoE and ageing was explored by quantifying longitudinal changes in ApoE expression in human ApoE3 and ApoE4- targeted replacement mice. Additionally, differences in markers of ageing between mice were examined. The results presented in this thesis highlight the fact that ApoE2 and ApoE3 outperform ApoE4. Out of the three isoforms, ApoE4 was the more prone to self-assembly, which is a pathogenic feature of LOAD. While no major differences could be spotted at the tissue level, significant dissimilarities appeared in how the structure of ApoE isoforms is affected by oxidative and reducing conditions, with results suggesting that ApoE2 and to a lesser extent ApoE3 could function as scavengers of oxidative agents. Finally, overall ApoE levels were found to be reduced in ApoE4 targeted-replacement mice compared to ApoE3-mice, especially at old age; and ApoE4 mice appeared to have increased markers of ageing compared to ApoE3 mice. Taken together, these result attest to the complexity of LOAD and show the great number of ways ApoE could be differentially implicated in its onset.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Neuroscience
Subjects: R Medicine > RC Internal medicine > RC0321 Neurosciences. Biological psychiatry. Neuropsychiatry > RC0438 Psychiatry, including Psychopathology > RC0513 Psychoses > RC0521 Dementia > RC0522 Presenile dementia > RC0523 Alzheimer's disease
Depositing User: Library Cataloguing
Date Deposited: 10 Dec 2019 08:00
Last Modified: 11 Jan 2022 11:12
URI: http://sro.sussex.ac.uk/id/eprint/88660

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