Institute of Nano Science and Technology, Mohali, Punjab 160062, India.
CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
ACS Appl Mater Interfaces. 2020 Sep 30;12(39):44180-44194. doi: 10.1021/acsami.0c13223. Epub 2020 Sep 15.
The aggregation of neurotoxic amyloid-β (Aβ) polypeptides into aberrant extracellular senile plaques is the major neuropathological hallmark of Alzheimer's disease (AD). Inhibiting aggregation of these peptides to control the progression of this deadly disease can serve as a viable therapeutic option. In the current work, inherently fluorescent theranostic dopamine-tryptophan nanocomposites (DTNPs) were developed and investigated for their amyloid inhibition propensity along with their ability to act as a cellular bioimaging agent in neuronal cells. The antiaggregation potency of the nanocomposites was further investigated against an in vitro established reductionist amyloid aggregation model consisting of a mere dipeptide, phenylalanine-phenylalanine (FF). As opposed to large peptide/protein-derived robust and high-molecular-weight amyloid aggregation models of Alzheimer's disease, our dipeptide-based amyloid model provides an edge over others in terms of the ease of handling, synthesis, and cost-effectiveness. Results demonstrated positive antiaggregation behavior of the DTNPs toward both FF-derived amyloid fibrils and preformed Aβ-peptide fibers by means of electron microscopic and circular dichroism-based studies. Our results further pointed toward the neuroprotective effects of the DTNPs in neuroblastoma cells against FF amyloid fibril-induced toxicity and also that they significantly suppressed the accumulation of Aβ42 oligomers in both cortex and hippocampus regions and improved cognitive impairment in an intracerebroventricular streptozotocin (ICV-STZ)-induced animal model of dementia. Besides, DTNPs also exhibited excellent fluorescent properties and light up the cytoplasm of neuroblastoma cells when being coincubated with cells, confirming their ability to serve as an intracellular bioimaging agent. Overall, these results signify the potency of the DTNPs as promising multifunctional theranostic agents for treating AD.
神经毒性淀粉样蛋白-β（Aβ）多肽的聚集形成异常的细胞外老年斑是阿尔茨海默病（AD）的主要神经病理学标志。抑制这些肽的聚集以控制这种致命疾病的进展，可以作为一种可行的治疗选择。在目前的工作中，开发了具有内在荧光的治疗诊断多巴胺-色氨酸纳米复合材料（DTNPs），并研究了它们抑制淀粉样蛋白聚集的倾向，以及它们在神经元细胞中作为细胞生物成像剂的能力。还进一步研究了纳米复合材料对体外建立的简化淀粉样蛋白聚集模型的抗聚集能力，该模型仅由二肽苯丙氨酸-苯丙氨酸（FF）组成。与阿尔茨海默病的大肽/蛋白质衍生的稳健和高分子量淀粉样蛋白聚集模型相比，我们的基于二肽的淀粉样蛋白模型在易于处理、合成和成本效益方面具有优势。结果表明，DTNPs 通过电子显微镜和基于圆二色性的研究对 FF 衍生的淀粉样原纤维和预先形成的 Aβ-肽纤维表现出积极的抗聚集行为。我们的结果进一步表明，DTNPs 对神经母细胞瘤细胞具有神经保护作用，可以抵抗 FF 淀粉样纤维诱导的毒性，并且它们还显著抑制了 Aβ42 低聚物在皮质和海马区的积累，并改善了脑室注射链脲佐菌素（ICV-STZ）诱导的痴呆动物模型中的认知障碍。此外，DTNPs 还表现出优异的荧光特性，当与细胞共孵育时，使神经母细胞瘤细胞的细胞质发光，证实了它们作为细胞内生物成像剂的能力。总的来说，这些结果表明 DTNPs 作为治疗 AD 的有前途的多功能治疗诊断试剂的潜力。
