The role of bacterial amyloid curli in Alzheimer's Disease

Temple Univ Of The Commonwealth, Philadelphia PA

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Abstract

Summary Deposition of amyloid proteins is associated with inflammatory responses in a number of complex illnesses, such as Alzheimer's disease (AD) and Parkinson's disease. In each disease, an amyloid fibril accumulates resulting in local inflammation. In addition to humans, bacteria also express amyloid proteins. Curli fibrils expressed by the commensal as well as pathogenic enteric bacteria, including Escherichia coli, Salmonella ssp are the best-characterized bacterial amyloids. Amyloid proteins, whether human or bacterial, do not share nucleotide or amino acid sequence homology. Nevertheless, all amyloid monomers fold into a common conserved cross-beta sheet structure, which facilitates the fibril formation. This fibrillar quaternary structure is important for many aspects of the physiology and pathogenicity of amyloid proteins. Intriguingly, small amount of preformed fibrils of the same or different origin (e.g. human or bacterial) have been shown to dramatically accelerate the polymerization process of a monomeric amyloid protein into fibrillar structures and deposits. This phenomenon is known as seeding/cross-seeding and is documented to occur between human-human amyloids, e.g. tau amyloid from AD and -synclein from Parkinson's disease, or human-bacterial amyloids, e.g. -synclein and curli. Since humans are continuously exposed to bacterial products through their microbiomes, as well occasionally exposed to the pathogenic bacteria, it is easy to postulate that humans are constantly exposed to bacterial amyloids. The objective of this application is to elucidate whether the presence of curli fibrils in the gastrointestinal tract or systemic presentation by invasive pathogens could contribute to disease pathogenesis in AD.