Koppel Kairi, Tang Huayuan, Javed Ibrahim, Parsa Mehrdad, Mortimer Monika, Davis Thomas P, Lin Sijie, Chaffee Alan L, Ding Feng, Ke Pu Chun
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, USA.
Nanoscale. 2020 Jun 18;12(23):12317-12328. doi: 10.1039/d0nr02710c.
Type 2 diabetes (T2D) and Alzheimer's disease (AD) represent two most prevalent amyloid diseases with a significant global burden. Pathologically, T2D and AD are characterized by the presence of amyloid plaques consisting primarily of toxic human islet amyloid polypeptide (IAPP) and amyloid beta (Aβ). It has been recently revealed that the gut microbiome plays key functions in the pathological progression of neurological disorders through the production of bacterial endotoxins, such as lipopolysaccharide (LPS). In this study, we examined the catalytic effects of LPS on IAPP and Aβ amyloidoses, and further demonstrated their mitigation with zero-dimensional carbon quantum dots (CQDs). Whereas LPS displayed preferred binding with the N-terminus of IAPP and the central hydrophobic core and C-terminus of Aβ, CQDs exhibited propensities for the amyloidogenic and C-terminus regions of IAPP and the N-terminus of Aβ, accordingly. The inhibitory effect of CQDs was verified by an embryonic zebrafish model exposed to the peptides and LPS, where impaired embryonic hatching was rescued and production of reactive oxygen species in the organism was suppressed by the nanomaterial. This study revealed a robust synergy between LPS and amyloid peptides in toxicity induction, and implicated CQDs as a potential therapeutic against the pathologies of T2D and AD.
2型糖尿病（T2D）和阿尔茨海默病（AD）是两种最常见的淀粉样变性疾病，全球负担沉重。在病理上，T2D和AD的特征是存在主要由有毒的人胰岛淀粉样多肽（IAPP）和β淀粉样蛋白（Aβ）组成的淀粉样斑块。最近发现，肠道微生物群通过产生细菌内毒素（如脂多糖，LPS）在神经疾病的病理进展中发挥关键作用。在本研究中，我们研究了LPS对IAPP和Aβ淀粉样变的催化作用，并进一步证明了零维碳量子点（CQDs）对它们的缓解作用。LPS优先与IAPP的N端、Aβ的中央疏水核心和C端结合，而CQDs则分别倾向于与IAPP的淀粉样生成区域和C端以及Aβ的N端结合。通过暴露于肽和LPS的斑马鱼胚胎模型验证了CQDs的抑制作用，在该模型中，纳米材料挽救了受损的胚胎孵化，并抑制了生物体内活性氧的产生。这项研究揭示了LPS和淀粉样肽在毒性诱导方面的强大协同作用，并表明CQDs可能是治疗T2D和AD病理的潜在药物。
