Investigation of Designed Peptides for the Disruption of Bacterial and Mammalian Amyloid Systems

Abstract

Amyloid proteins are associated with an increasing number of human diseases. In amyloid systems, soluble proteins experience conformational changes that trigger aggregation into toxic soluble oligomers, then protofibrils, and eventually into insoluble amyloid fibrils. Synthetic α-sheet peptides inhibit amyloid formation by adopting a complementary conformation to the native protein structure and by binding toxic oligomers, including the β-amyloid peptide (Aβ) involved in Alzheimer’s Disease (AD). These α-sheet peptides not only inhibit amyloid fibrilization in mammalian amyloid diseases but also in bacteria, which produce functional amyloid proteins as part of their biofilm extracellular matrix. Here, we demonstrate that co-administration of α-sheet peptides with various antibiotics increases biofilm antibiotic susceptibility in both gram-negative and -positive bacteria. Additionally, the peptides are incorporated into a functionalized gauze for biofilm inhibition at a wound site and tethered to titanium dental implants to prevent oral biofilm infection. Next, the effects of the α-sheet peptides on Aβ in the context of AD were further examined. An increased rate of phagocytosis of Aβ oligomers in multiple cell lines was observed when cells were treated with α-sheet peptides. The α-sheet peptides were then administered alongside Aβ oligomers to transgenic mice that overexpress human tau. Intracranial injections of Aβ oligomers resulted in long-term behavioral impairments in the mice, whereas the peptide injections appeared to be safe and to reduce the anxiety induced by the intracranial injection of Aβ oligomers. In this dissertation, synthetic α-sheet peptides are first presented as novel amyloid inhibitors with proposed biomaterial applications for biofilm prevention. Finally, the peptides are investigated in the context of AD with implications for further elucidation of the disease mechanisms.