Polymer Therapeutics Lab., Centro de Investigación Príncipe Felipe (CIPF), Av. Eduardo Primo Yúfera 3, 46012 Valencia, Spain.
Grupo de Investigación FRESHAGE, Departamento de Fisiología, Facultad de Medicina, Univ.. Valencia, CIBERFES-ISCIII, INCLIVA, Av. Blasco Ibáñez 15, 46010 Valencia, Spain.
Sci Adv. 2021 Mar 26;7(13). doi: 10.1126/sciadv.abf9180. Print 2021 Mar.
Alzheimer's disease (AD), the most prevalent form of dementia, remains incurable mainly due to our failings in the search for effective pharmacological strategies. Here, we describe the development of targeted multimodal polypeptide-based nanoconjugates as potential AD treatments. Treatment with polypeptide nanoconjugates bearing propargylamine moieties and bisdemethoxycurcumin or genistein afforded neuroprotection and displayed neurotrophic effects, as evidenced by an increase in dendritic density of pyramidal neurons in organotypic hippocampal culture. The additional conjugation of the Angiopep-2 targeting moiety enhanced nanoconjugate passage through the blood-brain barrier and modulated brain distribution with nanoconjugate accumulation in neurogenic areas, including the olfactory bulb. Nanoconjugate treatment effectively reduced neurotoxic β amyloid aggregate levels and rescued impairments to olfactory memory and object recognition in APP/PS1 transgenic AD model mice. Overall, this study provides a description of a targeted multimodal polyglutamate-based nanoconjugate with neuroprotective and neurotrophic potential for AD treatment.
阿尔茨海默病（AD）是最常见的痴呆症形式，主要由于我们未能找到有效的药物治疗策略，目前仍然无法治愈。在这里，我们描述了靶向多模态多肽纳米缀合物作为潜在 AD 治疗方法的开发。用带有炔丙胺基团的多肽纳米缀合物和双去甲氧基姜黄素或染料木黄酮进行治疗，可提供神经保护作用，并显示出神经营养作用，这表现在器官培养的海马体中的锥体神经元树突密度增加。额外结合血管生成肽-2 靶向部分可增强纳米缀合物穿过血脑屏障的能力，并调节脑内分布，使纳米缀合物在包括嗅球在内的神经发生区域积聚。纳米缀合物治疗可有效降低神经毒性β淀粉样蛋白聚集物水平，并可挽救 APP/PS1 转基因 AD 模型小鼠的嗅觉记忆和物体识别损伤。总体而言，本研究描述了一种具有神经保护和神经营养潜力的靶向多模态聚谷氨酸基纳米缀合物，可用于 AD 的治疗。
