Department of Biomedical Engineering , Northwestern University , Evanston , Illinois 60208 , United States.
Simpson Querrey Institute , Northwestern University , Chicago , Illinois 60611 , United States.
Nano Lett. 2018 Oct 10;18(10):6237-6247. doi: 10.1021/acs.nanolett.8b02317. Epub 2018 Sep 13.
Brain-derived neurotrophic factor (BDNF), a neurotrophin that binds specifically to the tyrosine kinase B (TrkB) receptor, has been shown to promote neuronal differentiation, maturation, and synaptic plasticity in the central nervous system (CNS) during development or after injury and onset of disease. Unfortunately, native BDNF protein-based therapies have had little clinical success due to their suboptimal pharmacological properties. In the past 20 years, BDNF mimetic peptides have been designed with the purpose of activating certain cell pathways that mimic the functional activity of native BDNF, but the interaction of mimetic peptides with cells can be limited due to the conformational specificity required for receptor activation. We report here on the incorporation of a BDNF mimetic sequence into a supramolecular peptide amphiphile filamentous nanostructure capable of activating the BDNF receptor TrkB and downstream signaling in primary cortical neurons in vitro. Interestingly, we found that this BDNF mimetic peptide is only active when displayed on a peptide amphiphile supramolecular nanostructure. We confirmed that increased neuronal maturation is linked to TrkB signaling pathways by analyzing the phosphorylation of downstream signaling effectors and tracking electrical activity over time. Furthermore, three-dimensional gels containing the BDNF peptide amphiphile (PA) nanostructures encourage cell infiltration while increasing functional maturation. Our findings suggest that the BDNF mimetic PA nanostructure creates a highly bioactive matrix that could serve as a biomaterial therapy in injured regions of the CNS. This new strategy has the potential to induce endogenous cell infiltration and promote functional neuronal maturation through the presentation of the BDNF mimetic signal.
脑源性神经营养因子（BDNF）是一种神经营养因子，特异性结合酪氨酸激酶 B（TrkB）受体，已被证明可促进中枢神经系统（CNS）在发育过程中或损伤和疾病发作后的神经元分化、成熟和突触可塑性。不幸的是，由于其药理特性不理想，基于天然 BDNF 蛋白的治疗方法在临床上收效甚微。在过去的 20 年中，已经设计了 BDNF 模拟肽，目的是激活某些细胞途径，模拟天然 BDNF 的功能活性，但由于受体激活所需的构象特异性，模拟肽与细胞的相互作用可能受到限制。我们在这里报告了将 BDNF 模拟序列掺入能够在体外激活原代皮质神经元中的 BDNF 受体 TrkB 和下游信号的超分子肽两亲体丝状纳米结构中。有趣的是，我们发现这种 BDNF 模拟肽只有在展示在肽两亲体超分子纳米结构上时才具有活性。我们通过分析下游信号效应物的磷酸化和随时间跟踪电活性来确认增加的神经元成熟与 TrkB 信号通路有关。此外，含有 BDNF 肽两亲体（PA）纳米结构的 3D 凝胶可促进细胞渗透，同时增加功能成熟。我们的研究结果表明，BDNF 模拟 PA 纳米结构可创建一种高度生物活性的基质，可作为 CNS 损伤区域的生物材料治疗方法。这种新策略有可能通过呈现 BDNF 模拟信号来诱导内源性细胞渗透并促进功能性神经元成熟。
