Alzheimer's Disease (AD) is a neurodegenerative disorder that affects around 50 million people worldwide and causes cognitive decline, brain atrophy and death. Despite extensive basic and clinical studies and drug development efforts, currently no effective treatments are available for AD. The amyloid β (Aβ) peptide is neurotoxic and is tightly associated with AD pathology, but the molecular mechanism of its action remains unclear. There are various forms of Aβ in the brain, ranging from the full length Aβ1-42 to shorter peptides, such as a strongly toxic Aβ25-35 fragment. The Amyloid Cascade Hypothesis (ACH) postulated that extracellular Aβ deposits cause the disease. More recently, the soluble Aβ oligomers came into the focus of research as they proved to be the major neurotoxic entities. One of the mechanisms by which Aβ peptides, including Aβ25-35, kill neurons is membrane perforation and disruption of cellular homeostasis. Although direct membrane interaction and pore formation by Aβ has been documented, the detailed structural aspects of membrane pores remain elusive. Here, we quantitatively describe the structure of Aβ25-35 in aqueous buffer and in lipid environment, its binding to membranes, pore formation, and the details of membrane pores. We have shown that membrane binding of Aβ25-35 is electrostatically driven. Aβ25-35 forms β-barrel like structures ranging from hexamers to octamers and then assemble into supra-molecular structures forming calcium-conducting pores in the membrane with radius of 6 Å to 7 Å. The structural features of Aβ25-35 pores depend on the content of cholesterol in the membranes. Moreover, the aggregation and structural changes of a series of Aβ fragments have been analyzed to identify the segment(s) of highest propensity for fibrillogenesis that might serve as initiators of Aβ aggregation and conversion into toxic species. Finally, the structures of the full-length Aβ1-42 and a hypertoxic version pEAβ 3-42, in lipid environment have been analyzed by solid state nuclear magnetic resonance. Collectively, these studies will elucidate the structural details of membrane pores formed by Aβ peptides as targets for new anti-AD therapies.


If this is your thesis or dissertation, and want to learn how to access it or for more information about readership statistics, contact us at STARS@ucf.edu

Graduation Date





Tatulian, Suren


Doctor of Philosophy (Ph.D.)


College of Sciences



Degree Program





CFE0008087; DP0023226





Release Date

February 2021

Length of Campus-only Access

1 year

Access Status

Doctoral Dissertation (Campus-only Access)