Investigating dynamic structural and mechanical changes of neuroblastoma cells associated with glutamate-mediated neurodegeneration

Abstract

Glutamate-mediated neurodegeneration resulting from excessive activation of glutamate receptors is recognized as one of the major causes of various neurological disorders such as Alzheimer's and Huntington's diseases. However, the underlying mechanisms in the neurodegenerative process remain unidentified. Here, we investigate the real-time dynamic structural and mechanical changes associated with the neurodegeneration induced by the activation of N-methyl-D-aspartate (NMDA) receptors (a subtype of glutamate receptors) at the nanoscale. Atomic force microscopy (AFM) is employed to measure the three-dimensional (3-D) topography and mechanical properties of live SH-SY5Y cells under stimulus of NMDA receptors. A significant increase in surface roughness and stiffness of the cell is observed after NMDA treatment, which indicates the time-dependent neuronal cell behavior under NMDA-mediated neurodegeneration. The present AFM based study further advance our understanding of the neurodegenerative process to elucidate the pathways and mechanisms that govern NMDA induced neurodegeneration, so as to facilitate the development of novel therapeutic strategies for neurodegenerative diseases.

Nanoscale monitoring of drug actions on cell membrane using atomic force microscopy

“…Acta Pharmacologica Sinica npg stimulation of drugs [51][52][53] to assess the drug actions from the viewpoint of cell mechanics.…”

“…Studies in the past decade have demonstrated that cell mechanics play an important role in maintaining cellular physiological activities [53,63] . Cells sense external mechanical stimuli and convert them into intracellular chemical signals via proteins on the cell surface to regulate cellular physiological activities [64] .…”

“…In 2007, Lam et al [52] investigated the mechanical properties of leukemia cells (isolated from the blood of patients with diagnosed acute leukemia) in response to chemotherapy drugs (dexamethasone, daunorubicin), and the results showed that leukemia cell stiffness increased by nearly two orders of magnitude after exposure to dexamethasone or daunorubicin. N-methyl-D-aspartate (NMDA) specifically binds to the NMDA receptors in the cytomembrane that opens the ligand gated ion channel to facilitate Ca 2+ influx into the cell [53] . In 2014, Fang et al [53] investigated the effect of NMDA on SH-SY5Y human neuroblastoma cells from the viewpoint of cell elasticity, and the results showed that the cell Young's modulus significantly increased after the treatment of NMDA.…”

“…N-methyl-D-aspartate (NMDA) specifically binds to the NMDA receptors in the cytomembrane that opens the ligand gated ion channel to facilitate Ca 2+ influx into the cell [53] . In 2014, Fang et al [53] investigated the effect of NMDA on SH-SY5Y human neuroblastoma cells from the viewpoint of cell elasticity, and the results showed that the cell Young's modulus significantly increased after the treatment of NMDA. These studies provide novel insight into the effects of drugs and also facilitate the development of new therapeutic strategies for combating diseases such as cancer.…”

“…Researchers have shown that prolonged poking (200 s) of the cell can lead to the remodeling of the cell cytoskeleton, and thus the probing time should be limited during the measurements to avoid this effect [69] . In practice, when we investigate the effect of external stimuli such as drugs on the cellular elasticity, control experiments (eg, monitoring changes in the cellular elasticity without the addition of drugs) [51,53] are often required to determine the influence of tip poking on the cellular elasticity.…”