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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein

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The frontotemporal dementia mutation R406W blocks tau's interaction with the membrane in an annexin A2-dependent

Anne Gauthier-Kemper1, Carina Weissmann, Nataliya Golovyashkina

  • 1Department of Neurobiology, University of Osnabrück, Osnabrück, Germany.

The Journal of Cell Biology
|February 23, 2011
PubMed

Insights

The R406W tau mutation in Alzheimer's disease (AD) impairs membrane binding, not microtubule interaction. This defect involves annexin A2 (AnxA2), a protein crucial for linking membranes to the cytoskeleton.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Tau protein alterations are central to Alzheimer's disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17).
  • The R406W tau mutation, a cause of FTDP-17, leads to a tauopathy clinically similar to AD, but its functional consequences remain unclear.

Purpose of the Study:

  • To investigate the functional impact of the FTDP-17 tau mutation R406W.
  • To elucidate the molecular mechanisms underlying tau-related tauopathies.

Main Methods:

  • Investigated tau's interaction with microtubules and cell membranes.
  • Utilized tandem affinity purification and mass spectrometry to identify tau-binding partners.
  • Employed a yeast expression system to study tau-AnxA2 interactions.
  • Assessed the effects of calcium sequestration and AnxA2 knockdown on tau behavior.

Main Results:

  • The R406W mutation did not alter tau's interaction with microtubules.
  • Tau's ability to bind to membranes was abolished by the R406W mutation.
  • Loss of membrane binding led to reduced tau trapping at neurite tips and increased process length fluctuations.
  • Annexin A2 (AnxA2) was identified as a potential tau interaction partner.
  • Wild-type tau, but not R406W tau, interacted with AnxA2.
  • Calcium sequestration or AnxA2 knockdown reversed the differential trapping of wild-type and R406W tau.

Conclusions:

  • The R406W mutation's pathological effects stem from impaired membrane binding.
  • This impaired binding involves a functional interaction with AnxA2, acting as a membrane-cytoskeleton linker.
  • Understanding this mechanism provides insights into tauopathies like AD.

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