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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
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.
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.
- 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.