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Collagen Hydrogel Confinement of Amyloid-β Accelerates Aggregation and Reduces Cytotoxic Effects

35 Pages Posted: 23 Jul 2019 First Look: Accepted

See all articles by Laura W. Simpson

Laura W. Simpson

University of Maryland, Baltimore County (UMBC) - Department of Chemical, Biochemical and Environmental Engineering

Gregory L. Szeto

University of Maryland, Baltimore County (UMBC) - Department of Chemical, Biochemical and Environmental Engineering; University of Maryland - Marlene and Stewart Greenebaum Comprehensive Cancer Center

Hacene Boukari

Delaware State University - Division of Physical and Computational Sciences

Theresa A. Good

National Science Foundation - Division of Molecular and Cellular Biosciences

Jennie B. Leach

University of Maryland, Baltimore County (UMBC) - Department of Chemical, Biochemical and Environmental Engineering

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 very likely 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 β-sheet 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. These results, taken together with the many recent reports that 3D hydrogel cell cultures enable cell morphologies and epigenetic changes that are more similar to cells in vivo compared to 2D cultures, strongly suggest that AD drugs should be tested in 3D culture systems as a step along the development pathway towards new, more effective therapeutics.

Keywords: Alzheimer's disease, beta amyloid, aggregation, hydrogel, confinement

Suggested Citation

Simpson, Laura W. and Szeto, Gregory L. and Boukari, Hacene and Good, Theresa A. and Leach, Jennie B., Collagen Hydrogel Confinement of Amyloid-β Accelerates Aggregation and Reduces Cytotoxic Effects (2019). Available at SSRN: https://ssrn.com/abstract=3423492 or http://dx.doi.org/10.2139/ssrn.3423492

Laura W. Simpson (Contact Author)

University of Maryland, Baltimore County (UMBC) - Department of Chemical, Biochemical and Environmental Engineering

Baltimore, MD
United States

Gregory L. Szeto

University of Maryland, Baltimore County (UMBC) - Department of Chemical, Biochemical and Environmental Engineering

Baltimore, MD
United States

University of Maryland - Marlene and Stewart Greenebaum Comprehensive Cancer Center

Baltimore, MD
United States

Hacene Boukari

Delaware State University - Division of Physical and Computational Sciences

Dover, MD
United States

Theresa A. Good

National Science Foundation - Division of Molecular and Cellular Biosciences

Alexandria, VA
United States

Jennie B. Leach

University of Maryland, Baltimore County (UMBC) - Department of Chemical, Biochemical and Environmental Engineering ( email )

Baltimore, MD
United States

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