Supramolecular Nanostructure Activates TrkB Receptor Signaling of Neuronal Cells by Mimicking Brain-Derived Neurotrophic Factor

Abstract

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.

Small Molecules Organic Co‐Assemblies as Functional Nanomaterials

“…They have used peptide sequences as well as functionalized monosaccharides , . They found that the functional sequences were more active when co‐assembled into the nanostructures than on their free states, supporting the use of the nanofibers scaffold . The ratio of functionalized PA in the co‐assembly and the linker length between the active group and the structural part of the functional monomer is critical for their bioactivity (Figure b) , …”

“…The inclusion of the structural sequence in the active monomers facilitates their incorporation into the nanostructures in a random way that can get disruptive at high percentages of the active monomer if the epitope has a destabilizing effect in the structure . This type of homo‐co‐assemblies has been used to incorporate active sequences to target proteins for neuronal cell maturation,, bone generation, and cartilage regeneration . They have used peptide sequences as well as functionalized monosaccharides , .…”

Kaempferide prevents cognitive decline via attenuation of oxidative stress and enhancement of brain‐derived neurotrophic factor/tropomyosin receptor kinase B/cAMP response element‐binding signaling pathway

“…Phosphorylated and total CREB proteins were decreased in both the cytoplasm and nucleus of Aβ‐treated cells (Rosa & Fahnestock, ). BDNF and its receptor, TrkB, are widely expressed in the brain and participate in a series of intracellular signaling processes, neuronal protection and survival, axonal and dendritic morphology, and synaptic plasticity (Edelbrock, Alvarez, Simkin, & Fyrner, ) The increased phosphorylation of TrkB at Thr515, through which BDNF exerts its neuronal protective functions, consists with increased expression of BDNF. The activated TrkB interacts with and phosphorylates several intracellular targets, including PI3K/Akt, Ras/MAPK/ERK, and CaM signal pathways.…”

Advanced Bottom‐Up Engineering of Living Architectures

“…The dispersion of hepatocyte‐like spheroids in a RAD16‐I peptide hydrogel showed that the generated 3D hydrogel significantly tailored cellular proliferation and presented matured differentiation profiles . Indeed, it has been recently disclosed that the bioactivity of amphiphile mimetic peptides (e.g., brain‐derived neurotrophic factor, BDNF) can be augmented in 3D hydrogels due to conformationally improved peptide–cell interactions in these systems, which not only encourages cell infiltration but increases functional maturation of the construct . A co‐assembly system of peptide amphiphiles designed to form nanofibers targeting cartilage repair was also proven promising for tissue regeneration based on a cell encapsulation approach .…”