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

Edelbrock, Alexandra N.; Àlvarez, Zaida; Simkin, Dina; Fyrner, Timmy; Chin, Stacey M.; Sato, Kohei; Kiskinis, Evangelos; Stupp, Samuel I.

doi:10.1021/acs.nanolett.8b02317

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

Journal Article · Thu Sep 13 00:00:00 EDT 2018 · Nano Letters

DOI:https://doi.org/10.1021/acs.nanolett.8b02317· OSTI ID:1482234

Edelbrock, Alexandra N. ^[1]; Àlvarez, Zaida ^[2]; Simkin, Dina ^[3]; ^[2]; Chin, Stacey M. ^[4]; ^[5]; Kiskinis, Evangelos ^[3]; ^[6]

Northwestern Univ., Evanston, IL (United States); Northwestern Univ., Chicago, IL (United States). Simpson Querrey Inst.
Northwestern Univ., Chicago, IL (United States). Simpson Querrey Inst.
Northwestern Univ., Chicago, IL (United States). Feinberg School of Medicine
Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States
Northwestern Univ., Chicago, IL (United States). Simpson Querrey Inst.; Northwestern Univ., Evanston, IL (United States)
Northwestern Univ., Evanston, IL (United States); Northwestern Univ., Chicago, IL (United States). Simpson Querrey Inst. and Dept. of Medicine

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. As such, this new strategy has the potential to induce endogenous cell infiltration and promote functional neuronal maturation through the presentation of the BDNF mimetic signal.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC); US Army Research Office (ARO); US Army Medical Research Materiel Command; National Science Foundation (NSF); National Cancer Institute (NCI); State of Illinois; International Institute for Nanotechnology (IIN); Northwestern University; E.I. DuPont de Nemours & Co.; The Dow Chemical Company; National Institutes of Health (NIH); National Institute of Biomedical Imaging and Bioengineering (NIBIB); Les Turner ALS Foundation; Muscular Dystrophy Association; Dravet Foundation; National Institute of Neurological Disorders and Stroke (NINDS); Beatriu de Pinós Fellowship; Paralyzed Veterans of America (PVA) Research Foundation

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1482234

Journal Information:: Nano Letters, Journal Name: Nano Letters Journal Issue: 10 Vol. 18; ISSN 1530-6984

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
BDNF mimetic
TrkB receptor
maturation
nanostructure
neurons
peptide amphiphile

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

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