The role of bacterial amyloid curli in Alzheimer's Disease

细菌淀粉样蛋白卷曲在阿尔茨海默病中的作用

基本信息

批准号：
10714005
负责人：
Cagla Tukel
金额：
$ 13.75万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714005
关键词：
3xTg-AD mouse Acceleration Alzheimer&apos s Disease Alzheimer&apos s disease model Amino Acid Sequence Homology Amyloid Amyloid Fibrils Amyloid Proteins Amyloid beta-Protein Amyloid deposition Amyloidosis Animals Bacteria Behavior Brain Complex Deposition Development Disease Disease Progression Dose Enterobacteriaceae Escherichia coli Exposure to Gastrointestinal tract structure Gliosis Human Immune response In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Leaky Gut Link Measures Microbial Biofilms Molecular Conformation Molecular Profiling Mus Non-Insulin-Dependent Diabetes Mellitus Nucleotides Onset of illness Oral Oral Administration Outcome Parkinson Disease Pathogenesis Pathogenicity Physiology Polymers Process Reporting Role Salmonella Salmonella typhimurium Sodium Dextran Sulfate Source Structure TLR1 gene TLR2 gene Testing alpha synuclein beta pleated sheet biophysical properties commensal bacteria cytotoxic cytotoxicity enteric infection gut bacteria gut microbiome in vivo innovation microbiome monomer mouse model mutant novel pathogen pathogenic bacteria polymerization pre-formed fibril public health relevance tau Proteins

项目摘要

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.