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

• 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
• 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' s Disease; Alzheimer' 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

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.

总结 淀粉样蛋白的沉积与许多复杂疾病的炎症反应有关， 如阿尔茨海默病（AD）和帕金森病。在每一种疾病中，淀粉样纤维 导致局部炎症。除了人类，细菌也表达淀粉样蛋白。卷曲纤维 由大肠杆菌以及致病性肠道细菌表达，包括大肠杆菌、沙门氏菌 是最具特征的细菌淀粉样蛋白。 淀粉样蛋白，无论是人类还是细菌，不共享核苷酸或氨基酸序列同源性。 然而，所有的淀粉样蛋白单体折叠成共同的保守的交叉β折叠结构，这促进了淀粉样蛋白的形成。 纤维的形成。这种纤维状四级结构对于生理学的许多方面都很重要， 淀粉样蛋白的致病性。有趣的是，少量相同或不同来源的预制原纤维 (e.g.人或细菌）已经显示出显著加速单体聚合过程， 淀粉样蛋白转化成纤维状结构并沉积。这种现象被称为播种/交叉播种， 有记录表明存在于人与人之间的淀粉样蛋白，例如AD的tau淀粉样蛋白和帕金森氏症的β-synclein 疾病，或人细菌淀粉样蛋白，例如β-synclein和curli。由于人类持续暴露于 细菌产品通过其微生物组，以及偶尔接触到致病菌，很容易 假设人类一直暴露在细菌淀粉样蛋白中。 本申请的目的是阐明胃肠道中卷曲原纤维的存在是否 侵入性病原体的全身或全身表现可能有助于AD的疾病发病机制。