Terasaki Institute for Biomedical Innovation (TIBI), 1018 Westwood Blvd, Los Angeles, CA, USA.
Terasaki Institute for Biomedical Innovation (TIBI), 1018 Westwood Blvd, Los Angeles, CA, USA; BIOMATEN, Center of Excellence in Biomaterials and Tissue Engineering Middle East Technical University, Ankara 06800, Turkey.
Acta Biomater. 2024 Jul 15;183:89-100. doi: 10.1016/j.actbio.2024.05.020. Epub 2024 May 25.
Self-assembling peptide-based hydrogels have become a highly attractive scaffold for three-dimensional (3D) in vitro disease modeling as they provide a way to create tunable matrices that can resemble the extracellular matrix (ECM) of various microenvironments. Alzheimer's disease (AD) is an exceptionally complex neurodegenerative condition; however, our understanding has advanced due to the transition from two-dimensional (2D) to 3D in vitro modeling. Nonetheless, there is a current gap in knowledge regarding the role of amyloid structures, and previously developed models found long-term difficulty in creating an appropriate model involving the ECM and amyloid aggregates. In this report, we propose a multi-component self-assembling peptide-based hydrogel scaffold to mimic the amyloid-beta (β) containing microenvironment. Characterization of the amyloid-β-mimicking hydrogel (Col-HAMA-FF) reveals the formation of β-sheet structures as a result of the self-assembling properties of phenylalanine (Phe, F) through π-π stacking of the residues, thus mimicking the amyloid-β protein nanostructures. We investigated the effect of the amyloid-β-mimicking microenvironment on healthy neuronal progenitor cells (NPCs) compared to a natural-mimicking matrix (Col-HAMA). Our results demonstrated higher levels of neuroinflammation and apoptosis markers when NPCs were cultured in the amyloid-like matrix compared to a natural brain matrix. Here, we provided insights into the impact of amyloid-like structures on NPC phenotypes and behaviors. This foundational work, before progressing to more complex plaque models, provides a promising scaffold for future investigations on AD mechanisms and drug testing. STATEMENT OF SIGNIFICANCE: In this study, we engineered two multi-component hydrogels: one to mimic the natural extracellular matrix (ECM) of the brain and one to resemble an amyloid-like microenvironment using a self-assembling peptide hydrogel. The self-assembling peptide mimics β-amyloid fibrils seen in amyloid-β protein aggregates. We report on the culture of neuronal progenitor cells within the amyloid-mimicking ECM scaffold to study the impact through marker expressions related to inflammation and DNA damage. This foundational work, before progressing to more complex plaque models, offers a promising scaffold for future investigations on AD mechanisms and drug testing.
自组装肽基水凝胶已成为三维（3D）体外疾病建模的极具吸引力的支架，因为它们提供了一种创建可调节基质的方法，该基质可以模拟各种微环境的细胞外基质（ECM）。阿尔茨海默病（AD）是一种极其复杂的神经退行性疾病；然而，由于从二维（2D）到 3D 体外建模的转变，我们对其的理解已经有所提高。尽管如此，对于淀粉样结构的作用，我们目前还存在知识上的差距，并且以前开发的模型在创建涉及 ECM 和淀粉样蛋白聚集的合适模型方面一直存在困难。在本报告中，我们提出了一种多组分自组装肽基水凝胶支架，以模拟含有淀粉样β（β）的微环境。对淀粉样β模拟水凝胶（Col-HAMA-FF）的表征表明，由于苯丙氨酸（Phe，F）通过残基的π-π堆积形成β-折叠结构，从而模拟了淀粉样β蛋白纳米结构，因此该水凝胶具有自组装特性。我们研究了与天然模拟基质（Col-HAMA）相比，淀粉样β模拟微环境对健康神经祖细胞（NPC）的影响。与天然脑基质相比，当 NPC 在类淀粉样基质中培养时，我们的结果表明神经炎症和细胞凋亡标志物的水平更高。在这里，我们深入了解了淀粉样结构对 NPC 表型和行为的影响。在进行更复杂的斑块模型之前，这项基础工作为 AD 机制和药物测试的未来研究提供了有前途的支架。 意义声明：在这项研究中，我们设计了两种多组分水凝胶：一种用于模拟大脑的天然细胞外基质（ECM），另一种用于使用自组装肽水凝胶模拟类淀粉样微环境。自组装肽模拟了淀粉样β蛋白聚集体中存在的β-淀粉样纤维。我们报告了在类淀粉样 ECM 支架中培养神经元祖细胞的情况，以通过与炎症和 DNA 损伤相关的标志物表达来研究其影响。在进行更复杂的斑块模型之前，这项基础工作为 AD 机制和药物测试的未来研究提供了有前途的支架。
