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Related Experiment Videos

Alzheimer disease hyperphosphorylated tau aggregates hydrophobically

G C Ruben1, T L Ciardelli, I Grundke-Iqbal

  • 1Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire 03755, USA. George.C.Ruben@Dartmouth.Edu

Synapse (New York, N.Y.)
|November 5, 1997
PubMed
Summary

Alzheimer's disease tau tangles may form due to hydrophobic interactions, not beta-sheet content. Hyperphosphorylated tau protein aggregates via a mechanism similar to elastin, driven by its altered hydrophobic character.

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Area of Science:

  • Biochemistry
  • Neuroscience
  • Protein Chemistry

Background:

  • Alzheimer's disease (AD) is characterized by neurofibrillary tangles formed by hyperphosphorylated tau protein (AD P-tau).
  • The precise chemical interactions driving tau aggregation and synaptic dysfunction remain unclear.
  • Known aggregation factors include beta-sheet formation, ionic bridges, and hydrophobic associations.

Purpose of the Study:

  • To investigate the chemical interactions responsible for AD P-tau aggregation into neurofibrillary tangles.
  • To determine the role of beta-sheet content versus hydrophobic interactions in tau aggregation.
  • To explore the influence of phosphorylation on tau's structural properties and aggregation propensity.

Main Methods:

  • Correlated transmission electron microscopy (TEM) images of tau aggregation with varying beta-sheet percentages.

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  • Utilized circular dichroism (CD) spectroscopy at different temperatures (5-85°C) to analyze secondary structures.
  • Examined AD P-tau, dephosphorylated AD P-tau, and various tau constructs (recombinant human tau, bovine tau).
  • Employed buffers to block ionic bridges and estimated secondary structures using the Lincomb algorithm.

    • Main Results:

    • No direct correlation was found between beta-sheet content and tau aggregation.
    • An inverse temperature transition (Ti) was observed in CD spectra for most tau preparations.
    • AD P-tau exhibited a significantly lower Ti (24.5-28°C) compared to dephosphorylated or non-pathological tau variants (32-38°C).
    • This low Ti for AD P-tau suggests increased hydrophobic character, similar to elastin.

    Conclusions:

    • Hydrophobic interactions, rather than beta-sheet content, are likely the primary driver of AD P-tau aggregation.
    • Hyperphosphorylation of tau neutralizes its basic character, exposing hydrophobic regions.
    • The aggregation mechanism of AD P-tau may involve hydrophobic coalescence at temperatures near body heat, analogous to elastin behavior.