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Title: Reactive oxygen species in Alzheimer's disease : studies of amyloid-beta-copper and apolipoprotein E
Author: Girvan, Paul
ISNI:       0000 0004 9356 7291
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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There are many hypotheses for the cause of Alzheimer’s disease. This thesis explores one such hypothesis, the metals hypothesis, and attempts to do so from a kinetic point of view. The metals hypothesis posits that Amyloid-b (Ab) can bind intrinsic metals within the brain, causing increased Ab oligomerisation, and (in the case of binding copper or iron) is able to be a source of reactive oxygen species (ROS), via redox cycling of the Ab-metal complex. In the first part of this thesis I draw comparisons between wild-type Ab and disease prone mutants, providing evidence that the disease mutants have 50% higher copper assisted dimerisation rate constants, compared to the wild-type Ab. In doing so I try to highlight the beneficial insights that a kinetic understand can afford. I explore the kinetic mechanism of AbCu redox cycling, attempting to address on what timescale the process occurs. I show that the reduction step is fairly rapid (tens of millisecond timescale), and follows a conformational selection mechanism. But that redox cycling is ultimately limited by the relatively slow oxidation. Looking further at the role of AbCu in ROS generation, I shown that AbCu is almost twice as efficient at causing lipid membrane peroxidation than uncomplexed Cu. This increased efficiency is surprising considering uncomplexed Cu can generate ROS much more rapidly than AbCu. Finally, this thesis moves on to look at apolipoprotein E (apoE), which is the biggest genetic risk factor for developing late onset AD. I explore the role of apoE as a lipoprotein and show that it displays antioxidant effects, protecting against lipid peroxidation.
Supervisor: Ying, Liming ; Baldwin, Geoff ; Brooks, Nick ; Barahona, Mauricio Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral