Therapeutic approaches to ApoE

Kraft, Lucas (2019) Therapeutic approaches to ApoE. Doctoral thesis (PhD), University of Sussex.

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Abstract

Apolipoprotein E4 (ApoE4) is the major genetic risk factor in Alzheimer's disease (AD) and homozygous individuals are at 12-fold greater risk developing the disorder. Three ApoE isoforms exist that differ by a cysteine-arginine interchange at sites 112 and 158. While the most common ApoE3 variant has a cysteine at site 112 and an arginine at site 158, ApoE2 has two cysteines and ApoE4 two arginines, respectively. The difference in primary structure is believed to alter ApoE tertiary/quaternary structure and its function and is presumably therefore responsible for ApoE4's increased risk for AD. However, the exact mechanism whereby ApoE4 differs functionally from ApoE3 (and ApoE2) is still elusive. In this thesis, isoform dependent differences in the binding ability to heparin, a natural analogue to heparan sulphate proteoglycans (HSPGs) that are physiological receptors of ApoE and important in brain lipoprotein metabolism, as well as new ApoE tool compounds are identified. ApoE4 binds stronger to heparin compared to ApoE2 and ApoE3 and induces substantial conformational changes as measured using small angle X-ray scattering (SAXS). The isoform-dependent difference in the heparin interaction suggests altered ApoE4 binding ability to HSPGs. Meanwhile, L-Thyroxine and it's analogue Tafamidis, as well as the selective estrogen receptor modulators (SERMs) Clomiphene, Tamoxifen, Toremifene, and the non-steroidal anti-inflammatory drug (NSAID) Meclofenamic acid were identified as novel ApoE binders by biophysical screening using the Corning® Epic® label-free, followed by microscale thermophoresis (MST) and isothermal titration calorimetry (ITC). Although none of these drugs showed selectivity for the ApoE4 versus ApoE2 and ApoE3 isoforms, they can nevertheless be used to investigate ApoE function and may also provide starting points for future attempts to identify and develop molecules which interact selectively with ApoE4 and which might therefore be of therapeutic utility.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QP Physiology > QP0091 Blood > QP0099.3 Special constituents, A-Z > QP0099.3.A65 Apolipoproteins
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
R Medicine > RM Therapeutics. Pharmacology > RM0300 Drugs and their actions
Depositing User: Library Cataloguing
Date Deposited: 08 May 2019 10:57
Last Modified: 08 Jun 2020 07:04
URI: http://sro.sussex.ac.uk/id/eprint/83615

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