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Post-translational modifications of beta-amyloid modulate its effect on cell mechanical properties and influence

Kseniya B Varshavskaya1, Evgeny P Barykin1, Roman V Timoshenko2

  • 1Engelhardt Institute of Molecular Biology, Moscow, Russia.

Frontiers in Molecular Neuroscience
|November 29, 2024
PubMed

Insights

Post-translational modifications of beta-amyloid (Aβ) impact Alzheimer's disease (AD) pathogenesis. Different Aβ isoforms alter neuronal cell mechanics and reactive oxygen species (ROS) levels via distinct signaling pathways.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Cell Biology

Background:

  • Post-translational modifications (PTMs) of beta-amyloid (Aβ) are implicated in Alzheimer's disease (AD) pathogenesis.
  • Aβ isoforms, like phosphorylated Ser8 (pS8-Aβ42) and isomerized Asp7 (iso-Aβ42), exhibit altered properties and in vivo presence.
  • Differential pathogenicity of Aβ isoforms may stem from distinct signaling cascades affecting cellular mechanical properties.

Purpose of the Study:

  • To investigate the impact of different Aβ isoforms on the mechanical properties (Young's modulus) and reactive oxygen species (ROS) levels of neuronal cells.
  • To compare the effects of unmodified Aβ42, pS8-Aβ42, and iso-Aβ42 on SH-SY5Y cells.
  • To analyze the modulation of signaling proteins involved in actin cytoskeleton regulation by various Aβ isoforms.

Main Methods:

  • Correlative scanning ion-conductance microscopy (SICM) was employed to measure cell Young's modulus.
  • Pt-nanoelectrodes were used to assess reactive oxygen species (ROS) levels.
  • Western blot analysis was performed to examine the levels of signaling proteins (cofilin, GSK3β, LIMK, ERK, p38).

Main Results:

  • Unmodified Aβ42 significantly increased cell Young's modulus after 4 hours.
  • pS8-Aβ42 induced the most substantial increase in cell stiffness and ROS levels after 24 hours.
  • Distinct Aβ isoforms differentially affected cofilin, GSK3β, LIMK, ERK, and p38 signaling pathways.

Conclusions:

  • PTMs of Aβ modulate its interaction with neuronal cells.
  • Aβ isoforms trigger different signaling cascades, leading to altered cellular mechanical properties and ROS production.
  • These findings highlight the role of Aβ modifications in AD pathogenesis through mechanotransduction pathways.
Keywords:
Alzheimer’s diseaseROSactin cytoskeletonbeta-amyloidcofilinpost-translational modificationsprotein kinasesscanning ion-conductance microscopy

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