Date of Graduation


Document Type


Degree Type



Eberly College of Arts and Sciences



Committee Chair

Justin Legleiter

Committee Co-Chair

Johnathan Boyd

Committee Member

Johnathan Boyd

Committee Member

Terry Gullion

Committee Member

Blake Mertz

Committee Member

Peng Li


Alzheimer’s disease (AD) is a neurodegenerative condition afflicting 5.7 million Americans with no effective treatments. The pathology of AD is described by the formation of neurotoxic oligomers formed by the self-assembly of amyloid-β (Aβ). The affinity of oligomers for cellular membranes disrupts calcium homeostasis and is believed to be the underlying cause of neurotoxicity; however, due to the metastability of oligomers, it has been difficult to understand their role in membrane interactions and self-assembly. Here we utilize post translational modifications (PTM) to understand the role of specific amino acids on Aβ40-membrane interactions and self-assembly. We employ ThT, AFM, CD, and polydiacetylene assays (PDA) to determine how PTMs of Met35, Lys28, and Lys16 affect the aggregation rates, population distributions, morphologies, and secondary structure of Aβ40 in the presence or absence of a model membrane system, total brain lipid extract (TBLE). Our results show that oxidative environments promote the selective oxidation of Met35 (Met35[O]). Decreases in the magnitude of Aβ40 aggregation was observed along with an inhibition of oligomer structural transitions to fibrils. In the presence of total brain lipid extracts (TBLE), Met35[O] showed increased aggregation rates relative to Aβ40 and reduced peptide-membrane interactions. Isolation of oxidative effects on TBLE and Aβ40 showed that the oxidation of the membrane was responsible for reductions in peptide-membrane interactions. Subsequent studies chemically acetylated Lys16 and Lys28 to understand how the removal of lysine’s cationic properties alters Aβ self-assembly and membrane-binding. Here we report that lower levels of acetylation, predominantly affecting Lys16, reduced fibrilization and oligomerization of Aβ40 while higher levels of acetylation affecting both Lys16 and Lys28 dramatically inhibited fibril formation and reduced oligomerization. In the presence of TBLE, aggregation of Aβ40 was observed even under higher levels of acetylation. Under the influence of the membrane, fibril aggregates of Aβ40 were observed with higher levels of acetylation producing annular aggregates suggesting the promotion of secondary aggregation pathways. Additionally, the magnitude of the peptide-membrane interactions of acetylated Aβ and PDA/TBLE vesicles were reduced but not absent. Collectively, these results highlight the role specific amino acids play in the assembly of Aβ, and how the presence of membranes modulates peptide-membrane interactions and influence aggregation pathways.