Phosphorylation in two discrete tau domains regulates a stepwise process leading to postsynaptic dysfunction.

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Tau protein is crucial for neuronal function, but its hyperphosphorylation in neurodegenerative diseases like Alzheimer's leads to synaptic dysfunction.
• Mislocalization of tau to dendritic spines and subsequent postsynaptic deficits are early consequences of tau phosphorylation.
• Specific phosphorylation sites driving these abnormalities remained largely unelucidated.

Purpose of the Study:

• To identify the specific phosphorylation sites in tau protein responsible for mislocalization to dendritic spines.
• To elucidate the phosphorylation sites mediating postsynaptic dysfunction.
• To understand the sequential events and kinase involvement in tau-mediated synaptic pathology.

Main Methods:

• Primary neuronal cultures (rat hippocampal neurons) were utilized.
• Advanced imaging techniques were employed to visualize tau localization.
• Electrophysiological recordings assessed synaptic function, particularly AMPA receptor activity.

Main Results:

• Tau mislocalization to dendritic spines is dependent on phosphorylation at Ser396 or Ser404 in the C-terminal domain.
• Postsynaptic dysfunction, specifically reduced AMPA receptor function, is linked to phosphorylation of residues in the N-terminal proline-rich region (Ser202, Thr205, Thr212, Thr217, Thr231).
• Inhibition of glycogen synthetase kinase 3β and cyclin-dependent kinase 5 is necessary to prevent tau mislocalization.

Conclusions:

• Tau pathology involves a sequential process with distinct phosphorylation events in different tau domains.
• C-terminal phosphorylation drives tau mislocalization, while N-terminal phosphorylation mediates postsynaptic dysfunction.
• These findings highlight differential phosphorylation as a key mechanism in tauopathies and suggest potential therapeutic targets.