(544b) The Effect of Peptoids On A? Aggregation and NF-?B Activation in Alzheimer's Disease Conference: AIChE Annual MeetingYear: 2013Proceeding: 2013 AIChE Annual MeetingGroup: Food, Pharmaceutical & Bioengineering DivisionSession: Fundamentals of Protein Folding in Diseases Time: Wednesday, November 6, 2013 - 3:33pm-3:51pm Authors: Wolf, L. M., University of South Carolina Moore, K. A., University of South Carolina Turner, J. P. Jr., University of Arkansas Moss, M., University of South Carolina Servoss, S. L., University of Arkansas Introduction: Alzheimer’s disease (AD) is a costly and devastating illness, affecting millions within the geriatric population. It is characterized by progressive neurological degeneration, manifesting in memory and cognitive impairment until eventual death. Although the exact mechanism for AD is currently unknown, it is hypothesized that the disease etiology lies within the aggregation and accumulation of the protein amyloid-β (Aβ), whose oligomeric and soluble fibril aggregates are toxic to neuronal cells. Thus, inhibition of Aβ aggregation is one therapeutic strategy. Peptoids are peptide derivatives that resist proteolytic degradation through a small structural modification in the backbone, leaving the side chain chemistry to largely resemble the original structure. This study examines the therapeutic potential of three peptoids, designed to mimic the KLVFF hydrophobic core of Aβ and incorporate a neutral, positive, or negative charge. These peptoids are assessed for their abilities to abate Aβ aggregation and reduce the NF-κB activation secondary to Aβ exposure. Materials and Methods: To examine the effect of peptoids on formation of large aggregates, SEC-purified Aβ1-40 monomer (20 μM) was incubated alone or with peptoid, aggregation was stimulated via agitation, and aggregate formation monitored via dot blot. To examine the effect of peptoids on the formation of small, oligomeric aggregates, Ab1-42 was solubilized in DMSO with or without peptoid and diluted into PBS to initiate oligomer formation. Oligomer size was assessed via Western blot and SDS-PAGE. In addition, oligomer hydrophobicity was examined using ANS fluorescence. Finally, the effect of peptoids on Ab physiological activity was assessed using activation of NF-kB in SHSY5Y human neuroblastoma cells. Results and Discussion: Ab aggregation in the presence of peptoids let to a reduction in the formation of fibrillar aggregates, with the positively charged peptoid having the most pronounced effect, significantly reducing aggregate formation by 57.4 ± 23.6%. (Fig 1) Ab oligomer formation was also affected by the presence of peptoids. All three peptoids reduced the quantity and size of oligomers formed, with the positively charged peptoid again possessing the greatest inhibitory capabilities. In contrast, only the neutral and positive peptoids also altered oligomer conformation, evidenced by the increased exposure of hydrophobic patches that elevated ANS fluorescence. These changes, however, had no significant impact on NF-kB activation. Conclusions: The three peptoids, which varied in charge, all exhibited inhibitory capabilities toward Ab aggregation; however the magnitude of that inhibitory capability and the manner of aggregate structure modification was dependent upon the peptoid charge. These results indicate that each of the peptoids interact differently with Ab. The peptoid-induced alterations in Ab aggregation, however, failed to decrease NF-kB activation. Thus, the peptoids examined here are ineffective as a treatment option for AD. However, the ability of peptoids to interact with Ab and alter aggregation suggests that other peptoid structures may qualify as a valid potential treatment for AD.