Pre-assembled tau filaments phosphorylated by GSK-3b form large tangle-like structures

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Neurofibrillary tangles composed of hyperphosphorylated tau protein are hallmarks of Alzheimer's disease (AD).
• The precise relationship between tau hyperphosphorylation and the formation of these tangles remains unclear.
• Tau pathology correlates with dementia severity in AD.

Purpose of the Study:

• To investigate the role of glycogen synthase kinase 3 beta (GSK-3beta) phosphorylation in tau tangle formation.
• To elucidate the mechanism by which tau phosphorylation influences polymer aggregation.

Main Methods:

• Utilized a cell-free in vitro model system to induce tau polymerization with arachidonic acid.
• Investigated the effect of GSK-3beta phosphorylation on pre-assembled tau filaments.
• Identified specific phosphorylation sites on tau filaments.

Main Results:

• GSK-3beta phosphorylation of tau filaments promotes their coalescence into neurofibrillary tangle-like structures.
• Five key phosphorylation sites (S199, T205, T231, S396, S404) were identified in phosphorylated filaments.
• These structures resemble tangles isolated from Alzheimer's disease brain tissue.

Conclusions:

• Phosphorylation of tau by GSK-3beta, either before or after polymerization, facilitates interactions between tau polymers.
• This interaction leads to the formation of stable clusters of tau filaments, contributing to Alzheimer's disease pathology.
• The findings provide insights into the molecular mechanisms driving tau aggregation in AD.