The Amyloid Cascade hypothesis provides a molecular-level mechanism for the etiology of Alzheimer’s Disease (AD) and proposes a central role for the genesis and aggregation of Aβ protein. Aβ protein is the product of cleavage of the amyloid precursor protein (APP), a single pass transmembrane protein, by secretases and is found in a variety of isoforms, with longer isoforms being linked to the early onset of AD. The isoform distribution is dependent on membrane environment, mutations, and post-translational modifications.
Lipid rafts are characterized by lipids induced into the liquid ordered phase by cholesterol, enhancing membrane thickness and lateral lipid density. Protein preference for rafts can control protein kinetics, and has been implicated in determining whether APP is processed by α– or β-secretase in the plasma membrane. In addition to inducing lipid rafts, cholesterol is hypothesized to directly modulate APP, the C-terminal fragment of APP (C99), and γ-secretase structure and function via direct interaction. To date, the molecular details involved in these fundamental events involved in Aβ genesis have yet to be resolved using experimental approaches, suggesting a critical role for computation.
This thesis presents the results of investigations of lipid phase separation and cholesterol and their effects on C99 using molecular dynamics simulation. To gain insight into the nature of lipid rafts, studies characterizing the simulation system sizes required for observation of phase separation, exploring the effect of cholesterol concentration on phase separation and lipid phases, and examining the applicability of different lipid and cholesterol models for the simulation of lipid phases and protein structure were performed. To gain insight into the fundamental properties of C99, studies exploring the structure of full-length C99, the interaction of cholesterol with C99 in various mutational states, the effect of membrane thickness on the C99 extramembrane domains, and the structure of C99 monomer and dimer were performed.
Taken together these studies advance our molecular-level understanding of the nature of cholesterol, the role of cholesterol in lipid phase separation, the effect of cholesterol on C99, and the structure of the full-sequence C99 monomer and dimer that play a critical role in the evolution of AD.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/44810 |
| Date | 27 June 2022 |
| Creators | Pantelopulos, George A. |
| Contributors | Straub, John E. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution 4.0 International, http://creativecommons.org/licenses/by/4.0/ |
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