Journal article
Reduced Extracellular Matrix Stiffness Prompts SH-SY5Y Cell Softening and Actin Turnover To Selectively Increase Aβ(1-42) Endocytosis
ACS chemical neuroscience, Vol.10(3), pp.1284-1293
03/20/2019
DOI: 10.1021/acschemneuro.8b00366
PMID: 30499651
Abstract
Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by the extracellular deposition of dense amyloid beta plaques. Emerging evidence suggests that the production of these plaques is initiated by the intracellular uptake and lysosomal preconcentration of the amyloid-beta (Aβ) peptide. All previous endocytosis studies assess Aβ uptake with cells plated on traditional tissue culture plastic; however, brain tissue is distinctly soft with a low-kPa stiffness. Use of an ultrastiff plastic/glass substrate prompts a mechanosensitive response (increased cell spreading, cell stiffness, and membrane tension) that potentially distorts a cell's endocytic behavior from that observed in vivo or in a more physiologically relevant mechanical environment. Our studies demonstrate substrate stiffness significantly modifies the behavior of undifferentiated SH-SY5Y neuroblastoma, where cells plated on soft (∼1 kPa) substrates display a rounded morphology, decreased actin polymerization, reduced adhesion (decreased β integrin expression), and reduced cell stiffness compared to cells plated on tissue culture plastic. Moreover, these neuroblastoma on softer substrates display a preferential increase in the uptake of the Aβ(1-42) compared to Aβ(1-40), while both isoforms display a clear stiffness-dependent increase of uptake relative to cells plated on plastic.
Considering the brain is a soft tissue that continues to soften with age, this mechanosensitive endocytosis of Aβ has significant implications for understanding age-related neurodegeneration and the mechanism behind Aβ uptake and fibril production. Overall, identifying these physical factors that contribute to the pathology of AD may offer novel avenues of therapeutic intervention.
Details
- Title: Subtitle
- Reduced Extracellular Matrix Stiffness Prompts SH-SY5Y Cell Softening and Actin Turnover To Selectively Increase Aβ(1-42) Endocytosis
- Creators
- Terra M Kruger - University of Iowa, Pharmaceutical Sciences and Experimental TherapeuticsKendra J Bell - University of Iowa, Pharmaceutical Sciences and Experimental TherapeuticsThiranjeewa I Lansakara - University of IowaAlexei V Tivanski - University of Iowa, ChemistryJonathan A Doorn - University of Iowa, Pharmaceutical Sciences and Experimental TherapeuticsLewis L Stevens - University of Iowa, Pharmaceutical Sciences and Experimental Therapeutics
- Resource Type
- Journal article
- Publication Details
- ACS chemical neuroscience, Vol.10(3), pp.1284-1293
- Publisher
- United States
- DOI
- 10.1021/acschemneuro.8b00366
- PMID
- 30499651
- ISSN
- 1948-7193
- eISSN
- 1948-7193
- Language
- English
- Date published
- 03/20/2019
- Academic Unit
- Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Chemistry; Medicinal and Natural Products Chemistry
- Record Identifier
- 9983985832202771
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