Growth and Toxicity of Amyloid β Polymorphs

dc.contributor.advisorVekilov, Peter G.
dc.contributor.committeeMemberWillson, Richard C.
dc.contributor.committeeMemberCirino, Patrick C.
dc.contributor.committeeMemberWolynes, Peter G.
dc.contributor.committeeMemberSherman, Michael B.
dc.creatorMafi, Sima 2023
dc.description.abstractAlzheimer's disease is a progressive neurodegenerative disorder and a leading cause of death worldwide. Despite extensive research, there is still no cure for the disease, possibly, due to insufficient understanding of the complex underlying causes. One of the hallmarks of Alzheimer’s is the accumulation of the protein fragment amyloid β (Aβ) into soluble aggregates or insoluble β-sheet-rich fibrils and plaques in the brain. Limited success in targeting these fibrils and plaques stems from a lack of understanding of the intricate process of Aβ fibrillization. We investigated the unknown mechanism of action of a potential Alzheimer’s drug candidate, bexarotene, on Aβ fibrillization using powerful techniques. Bulk kinetics studies suggested that bexarotene interferes with the primary nucleation step. Cryo-electron microscopy revealed that bexarotene enforces a distinct molecular structure (polymorph) for fibrils. For molecular-level insight, we employed atomic force microscopy (AFM) to monitor the growth of individual fibrils and directly determine the fibrils' growth rates. Bexarotene fibrils demonstrated a unique kinetics of growth, significantly slower than the fibrils generated without bexarotene. This behavior bolsters the two-step mechanism for the growth of fibrils, which is characterized by an intermediate complex at the tip of the fibril upheld by contacts different from the bulk fibril. Moreover, the addition of urea as a denaturant agent increased the solubility but did not affect the growth rates. The unusual response of the fibrils with distinct drug-enforced structure to urea indicates a unique intermediate state for growth. We further explored the correlation between fibril structure and growth rates by generating fibrils under different growth conditions. Fibrils formed in a quiescent condition display a distinct structure and slower kinetics of growth, analogous to the bexarotene-induced fibrils. Surprisingly, urea reduces the growth rates indicating the presence of a unique intermediate complex supported by non-hydrophobic contacts. Finally, we assessed the toxicity of different Aβ species in various fibril types. Importantly, we found that different fibril types induce varying levels of toxicity, and discovered that the species found in the supernatant, separated from the fibril solution, were more toxic than the peptides and fibrils, implying that these species may represent fragments of fibrils.
dc.description.departmentChemical and Biomolecular Engineering, William A. Brookshire Department of
dc.format.digitalOriginborn digital
dc.identifier.citationPortions of this work are found in: Mafimoghaddam, S.; Xu, Y.; Sherman, M. B.; Orlova, E. V.; Karki, P.; Orman, M. A.; Vekilov, P. G. Suppression of amyloid-β fibril growth by drug-engineered polymorph transformation. Journal of Biological Chemistry 2022, 298 (12). DOI: 10.1016/j.jbc.2022.102662.
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dc.subjectAlzheimer's, Amyloid β
dc.titleGrowth and Toxicity of Amyloid β Polymorphs
dcterms.accessRightsThe full text of this item is not available at this time because the student has placed this item under an embargo for a period of time. The Libraries are not authorized to provide a copy of this work during the embargo period.
local.embargo.terms2025-08-01 College of Engineering and Biomolecular Engineering, William A. Brookshire Department of Engineering of Houston of Philosophy


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