Collagen hydrogel confinement of Amyloid-β (Aβ) accelerates aggregation and reduces cytotoxic effects
| dc.contributor.author | Simpson, Laura W. | |
| dc.contributor.author | Szeto, Gregory L. | |
| dc.contributor.author | Boukari, Hacene | |
| dc.contributor.author | Good, Theresa A. | |
| dc.contributor.author | Leach, Jennie B. | |
| dc.date.accessioned | 2020-08-18T15:22:36Z | |
| dc.date.available | 2020-08-18T15:22:36Z | |
| dc.date.issued | 2020-05-25 | |
| dc.description.abstract | Alzheimer's disease (AD) is the most common form of dementia and is associated with the accumulation of amyloid-β (Aβ), a peptide whose aggregation has been associated with neurotoxicity. Drugs targeting Aβ have shown great promise in 2D in vitro models and mouse models, yet preclinical and clinical trials for AD have been highly disappointing. We propose that current in vitro culture systems for discovering and developing AD drugs have significant limitations; specifically, that Aβ aggregation is vastly different in these 2D cultures carried out on flat plastic or glass substrates vs. in a 3D environment, such as brain tissue, where Aβ confinement alters aggregation kinetics and thermodynamics. In this work, we identified attenuation of Aβ cytotoxicity in 3D hydrogel culture compared to 2D cell culture. We investigated Aβ structure and aggregation in solution vs. hydrogel using Transmission Electron Microscopy (TEM), Fluorescence Correlation Spectroscopy (FCS), and Thioflavin T (ThT) assays. Our results reveal that the equilibrium is shifted to stable extended β-sheet (ThT positive) aggregates in hydrogels and away from the relatively unstable/unstructured presumed toxic oligomeric Aβ species in solution. Volume exclusion imparted by hydrogel confinement stabilizes unfolded, presumably toxic species, promoting stable extended β-sheet fibrils. | en_US |
| dc.description.sponsorship | The authors would like to thank Tagide deCarvalho for her assistance with TEM imaging and Dr. S. Maiti (Tata Institute of Fundamental Research) for sharing the Maximum Entropy Method program for FCS. This work was supported by funding from the National Science Foundation (NSF) [EAGER CBET-1447057] and the National Institute of Health (NIH) [R01GM117159]. NSF provided support for TAG to contribute to this project through their Independent Research and Development program. Any opinion, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. | en_US |
| dc.description.uri | https://www.sciencedirect.com/science/article/abs/pii/S1742706120303007 | en_US |
| dc.format.extent | 10 pages | en_US |
| dc.genre | journal articles | en_US |
| dc.identifier | doi:10.13016/m2h5nv-nsjz | |
| dc.identifier.citation | Laura W. Simpson et al., Collagen hydrogel confinement of Amyloid-β (Aβ) accelerates aggregation and reduces cytotoxic effects, Acta Biomaterialia Volume 112, Pages 164-173 (2020), https://doi.org/10.1016/j.actbio.2020.05.030 | en_US |
| dc.identifier.uri | https://doi.org/10.1016/j.actbio.2020.05.030 | |
| dc.identifier.uri | http://hdl.handle.net/11603/19456 | |
| dc.language.iso | en_US | en_US |
| dc.publisher | Elsevier | en_US |
| dc.relation.isAvailableAt | The University of Maryland, Baltimore County (UMBC) | |
| dc.relation.ispartof | UMBC Chemical, Biochemical & Environmental Engineering Department Collection | |
| dc.relation.ispartof | UMBC Faculty Collection | |
| dc.rights | This item is likely protected under Title 17 of the U.S. Copyright Law. Unless on a Creative Commons license, for uses protected by Copyright Law, contact the copyright holder or the author. | |
| dc.rights | Public Domain Mark 1.0 | * |
| dc.rights | This work was written as part of one of the author's official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance with 17 U.S.C. 105, no copyright protection is available for such works under U.S. Law | |
| dc.rights.uri | http://creativecommons.org/publicdomain/mark/1.0/ | * |
| dc.title | Collagen hydrogel confinement of Amyloid-β (Aβ) accelerates aggregation and reduces cytotoxic effects | en_US |
| dc.type | Text | en_US |