Molecular Engineering Program, University of Washington, Seattle, WA, 98195-5610, USA.
Department of Neuroscience, University of Washington, Seattle, WA, 98195-5610, USA.
Sci Rep. 2024 Mar 5;14(1):5376. doi: 10.1038/s41598-024-55423-9.
Colocalization of microbial pathogens and the β-amyloid peptide (Aβ) in the brain of Alzheimer's disease (AD) patients suggests that microbial infection may play a role in sporadic AD. Aβ exhibits antimicrobial activity against numerous pathogens, supporting a potential role for Aβ in the innate immune response. While mammalian amyloid is associated with disease, many bacteria form amyloid fibrils to fortify the biofilm that protects the cells from the surrounding environment. In the microbial AD hypothesis, Aβ aggregates in response to infection to combat the pathogen. We hypothesize that this occurs through toxic Aβ oligomers that contain α-sheet structure and form prior to fibrillization. De novo designed α-sheet peptides specifically bind to the α-sheet structure present in the oligomers of both bacterial and mammalian amyloidogenic proteins to neutralize toxicity and inhibit aggregation. Here, we measure the effect of E. coli on Aβ, including upregulation, aggregation, and toxicity. Additionally, we determined the effect of Aβ structure on E. coli amyloid fibrils, or curli comprised of the CsgA protein, and biofilm formation. We found that curli formation by E. coli increased Aβ oligomer production, and Aβ oligomers inhibited curli biogenesis and reduced biofilm cell density. Further, curli and biofilm inhibition by Aβ oligomers increased E. coli susceptibility to gentamicin. Toxic oligomers of Aβ and CsgA interact via α-sheet interactions, neutralizing their toxicity. These results suggest that exposure to toxic oligomers formed by microbial pathogens triggers Aβ oligomer upregulation and aggregation to combat infection via selective interactions between α-sheet oligomers to neutralize toxicity of both species with subsequent inhibition of fibrillization.
微生物病原体与阿尔茨海默病（AD）患者大脑中的β-淀粉样肽（Aβ）的共定位表明，微生物感染可能在散发性 AD 中发挥作用。Aβ 对许多病原体表现出抗菌活性，支持 Aβ 在先天免疫反应中的潜在作用。虽然哺乳动物淀粉样蛋白与疾病有关，但许多细菌形成淀粉样纤维丝以增强生物膜的形成，从而保护细胞免受周围环境的影响。在微生物 AD 假说中，Aβ 在受到感染时聚集以对抗病原体。我们假设这是通过含有α-折叠结构的毒性 Aβ 低聚物发生的，该低聚物在纤维化之前形成。新设计的α-折叠肽特异性结合存在于细菌和哺乳动物淀粉样蛋白原纤维的低聚物中的α-折叠结构，以中和毒性并抑制聚集。在这里，我们测量了大肠杆菌对 Aβ 的影响，包括上调、聚集和毒性。此外，我们还确定了 Aβ 结构对大肠杆菌淀粉样纤维丝或由 CsgA 蛋白组成的卷曲的影响，以及生物膜的形成。我们发现，大肠杆菌卷曲的形成增加了 Aβ 低聚物的产生，而 Aβ 低聚物抑制了卷曲的生物发生并降低了生物膜细胞密度。此外，Aβ 低聚物卷曲和生物膜的抑制增加了大肠杆菌对庆大霉素的敏感性。Aβ 和 CsgA 的毒性低聚物通过α-折叠相互作用相互作用，中和其毒性。这些结果表明，暴露于微生物病原体形成的毒性低聚物会触发 Aβ 低聚物的上调和聚集，以通过α-折叠低聚物之间的选择性相互作用来对抗感染，从而中和两种物种的毒性，随后抑制纤维化。
