Journal article
A Soft Mechanical Phenotype of SH-SY5Y Neuroblastoma and Primary Human Neurons Is Resilient to Oligomeric Aβ(1–42) Injury
ACS chemical neuroscience, Vol.11(6), pp.840-850
03/18/2020
DOI: 10.1021/acschemneuro.9b00401
PMCID: PMC7958432
PMID: 32058688
Abstract
Aggregated amyloid beta (Aβ) is widely reported to cause neuronal dystrophy and toxicity through multiple pathways: oxidative stress, disrupting calcium homeostasis, and cytoskeletal dysregulation. The neuro-cytoskeleton is a dynamic structure that reorganizes to maintain cell homeostasis in response to varying soluble and physical cues presented from the extracellular matrix (ECM). Due this relationship between cell health and the ECM, we hypothesize that amyloid toxicity may be directly influenced by physical changes to the ECM (stiffness and dimensionality) through mechanosensitive pathways, and while previous studies demonstrated that Aβ can distort focal adhesion signaling with pathological consequences, these studies do not address the physical contribution from a physiologically relevant matrix. To test our hypothesis that physical cues can adjust Aβ toxicity, SH-SY5Y human neuroblastoma and primary human cortical neurons were plated on soft and stiff, 2D polyacrylamide matrices or suspended in 3D collagen gels. Each cell culture was exposed to escalating concentrations of oligomeric or fibrillated Aβ(1–42) with MTS viability and lactate dehydrogenase toxicity assessed. Actin restructuring was further monitored in live cells by atomic force microscopy nanoindentation, and our results demonstrate that increasing either matrix stiffness or exposure to oligomeric Aβ promotes F-actin polymerization and cell stiffening, while mature Aβ fibrils yielded no apparent cell stiffening and minor toxicity. Moreover, the rounded, softer mechanical phenotype displayed by cells plated onto a compliant matrix also demonstrated a resilience to oligomeric Aβ as noted by a significant recovery of viability when compared to same-dosed cells plated on traditional tissue culture plastic. This recovery was reproduced pharmacologically through inhibiting actin polymerization with cytochalasin D prior to Aβ exposure. These studies indicate that the cell–ECM interface can modify amyloid toxicity in neurons and the matrix-mediated pathways that promote this protection may offer unique targets in amyloid pathologies like Alzheimer’s disease.
Details
- Title: Subtitle
- A Soft Mechanical Phenotype of SH-SY5Y Neuroblastoma and Primary Human Neurons Is Resilient to Oligomeric Aβ(1–42) Injury
- Creators
- Terra M Kruger - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of PharmacyKendra J Bell - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of PharmacyThiranjeewa I Lansakara - Department of ChemistryAlexei V Tivanski - Department of ChemistryJonathan A Doorn - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of PharmacyLewis L Stevens - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy
- Resource Type
- Journal article
- Publication Details
- ACS chemical neuroscience, Vol.11(6), pp.840-850
- DOI
- 10.1021/acschemneuro.9b00401
- PMID
- 32058688
- PMCID
- PMC7958432
- NLM abbreviation
- ACS Chem Neurosci
- ISSN
- 1948-7193
- eISSN
- 1948-7193
- Publisher
- American Chemical Society
- Grant note
- DOI: 10.13039/100000066, name: National Institute of Environmental Health Sciences, award: ES005605; DOI: 10.13039/100008893, name: University of Iowa
- Language
- English
- Date published
- 03/18/2020
- Academic Unit
- Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Chemistry; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984070481902771
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