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Aggregation of Microtubule Binding Repeats of Tau Protein is Promoted by Cu2

Soha Ahmadi1,2, Shaolong Zhu3,4, Renu Sharma1

  • 1Department of Physical and Environmental Science, University of Toronto Scarborough, 1265 Military Trail, Toronto, Ontario M1C 1A4, Canada.

ACS Omega
|April 20, 2019
PubMed

Insights

Copper (Cu2+) interaction with tau protein's microtubule binding repeats drives aggregation and reactive oxygen species (ROS) formation, key in Alzheimer's disease. Antioxidants do not prevent this copper-induced damage.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Alzheimer's disease pathogenesis involves tau aggregation and reactive oxygen species (ROS).
  • Microtubule (MT) binding repeats of tau protein are implicated in tau aggregation.

Purpose of the Study:

  • To investigate the role of Cu2+ interaction with tau's MT binding repeats in aggregation and ROS formation.
  • To elucidate the molecular mechanisms underlying copper-induced tau aggregation.

Main Methods:

  • Electrospray ionization mass spectrometry (ESI-MS) and Nuclear Magnetic Resonance (NMR) experiments.
  • Analysis of copper interaction with full-length MT binding repeats (R1-R4).
  • Assessment of antioxidant effects (ascorbate, glutathione) on copper-induced aggregation.

Main Results:

  • Cu2+ binding to R1-R4 tau repeats induces aggregation via Cys-based redox chemistry.
  • Disulfide-bridge dimerization of R2 and R3 occurs, leading to fibrillar structures.
  • Copper-bound MT repeats exhibit increased redox activity, generating ROS and causing cellular damage.
  • Ascorbate and glutathione failed to prevent Cu2+-induced R2/R3 aggregation.

Conclusions:

  • Copper interaction with tau MT binding repeats is a critical driver of tau aggregation and ROS production in Alzheimer's disease.
  • The findings reveal a novel molecular mechanism for tau aggregation and suggest the MT binding domain as a therapeutic target.

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