Amyloid Beta, Alzheimer's disease, oligomers, protein disulfide isomerase, oligomer reversal, amyloid toxcity


Neurotoxic aggregates of amyloid beta (Aβ) peptide contribute to the etiology of Alzheimer's disease (AD). Aβ1-42 forms oligomeric structures that undergo further aggregation into protofibrils and fibrils. Oligomeric Aβ1-42 is more toxic than monomers or mature fibrils. In this work, we used two distinct approaches to inhibit Aβ1-42 oligomerization and toxicity. First, seven distinct but overlapping Aβ fragments were used to identify their individual aggregation propensities and their effects on Aβ1-42 oligomerization and cytotoxicity. Studies on suppression of Aβ1-42 cytotoxicity by peptides, including those derived from Aβ1-42, have been conducted before, but peptides encompassing the whole Aβ1-42 sequence have not been systematically analyzed. Aβ1-42 was allowed to aggregate and form oligomeric assemblies in aqueous buffer for 4 h in the absence or presence of 2-fold molar excess of an Aβ fragment. Cytotoxicity analysis then recorded the impact of each fragment on Aβ1-42 cytotoxicity as well as the toxicity of the fragments themselves. An enzyme-linked immunosorbent assay that detects oligomeric Aβwas used to determine the effect of each fragment on Aβ1-42 oligomerization after 4 h of aggregation. Four fragments of Aβ1-42 inhibited the toxicity of oligomeric Aβ1-42 to various degrees, while two others conferred no cellular protection against Aβ1-42 toxicity. Interestingly, one fragment enhanced Aβ1-42 toxicity after 4 h of aggregation. Three of the four fragments that blocked Aβ1-42 toxicity partially disrupted oligomer formation, showing correlation between the inhibition of Aβ1-42 aggregation and the inhibition of cellular toxicity. Second, we examined whether protein disulfide isomerase (PDI), a chaperone mainly found in the endoplasmic reticulum, could reverse the oligomeric state of aggregated Aβ1-42 and thus its toxicity. Previous work has demonstrated that PDI inhibits Aβ1-42 aggregation at sub-stoichiometric concentrations. To assess PDI's effect on Aβ1-42 toxicity, Aβ1-42 was allowed to aggregate for 2 h before the addition of PDI at a 1:10 molar ratio of PDI to Aβ1-42 and then allowed to aggregate for another 2 h. MTS cytotoxicity assays using PC-12 cells showed that adding PDI 2 h after the start of aggregation improves cell survival. Through a differential centrifugation assay followed by Western blot, we qualitatively illustrated that PDI can reverse a 2 h aggregate of Aβ1-42 to the monomeric state. Overall, in this project we have learned that inhibiting the oligomeric assembly of Aβ1-42 directly decreases the effect of Aβ1-42 toxicity. Inhibition of Aβ1-42 toxicity was seen with both fragments derived from Aβ1-42 and PDI, shedding light into two novel approaches as possible therapeutics for AD.

Completion Date




Committee Chair

Teter, Ken; Tatulian, Suren


Master of Science (M.S.)


College of Medicine


Burnett School of Biomedical Sciences

Degree Program










In copyright

Release Date

May 2029

Length of Campus-only Access

5 years

Access Status

Masters Thesis (Campus-only Access)

Campus Location

Orlando (Main) Campus

Accessibility Status

Meets minimum standards for ETDs/HUTs

Restricted to the UCF community until May 2029; it will then be open access.