The Role of α-Sheet Structure in Bacterial and Mammalian Amyloidogenesis and its Implication in the Microbial Alzheimer’s Disease Hypothesis

Abstract

Mammalian amyloidogenesis is implicated in over 50 diseases and its formation is typically considered inherently pathological. Conversely, many bacteria utilize amyloid fibrils as a structural scaffold to fortify a surface bound 3D matrix known as a biofilm. Bacterial and mammalian amyloidogenesis involves the production of toxic, soluble α-sheet oligomers prior to the formation of nontoxic β-sheet fibrils. The existence of a conserved conformation in the toxic intermediates formed during amyloidogenesis presents a strategy to inhibit aggregation in the context of mammalian amyloid disease and bacterial infection. Here, de novo peptides that stably adopt α-sheet conformation are employed to inhibit bacterial and mammalian amyloid formation, neutralize the oligomeric toxicity of mammalian amyloid peptides, and structurally destabilize bacterial biofilms, rendering them more susceptible to antibiotics. The knowledge of a conserved amyloid inhibition mechanism by α-sheet peptides is also used to investigate the microbial Alzheimer’s disease hypothesis, providing insight into the molecular mechanisms that govern the role of amyloid-β in the innate immune response and positing an evolutionary role for mammalian amyloidogenesis in the defense against microbial infection.