Hyperphosphorylation and cleavage at D421 enhance tau secretion

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Tau pathology is a hallmark of Alzheimer's disease (AD), spreading predictably through the brain.
• Accumulation of tau in cerebrospinal fluid (CSF) is observed in AD patients, but mechanisms are unclear.
• Tau secretion by cells is a potential contributor to tau pathology propagation and CSF accumulation.

Purpose of the Study:

• To investigate the mechanisms of tau secretion from cells.
• To determine the characteristics of secreted tau, including phosphorylation and cleavage.
• To elucidate the role of tau phosphorylation and cleavage in its secretion.

Main Methods:

• Overexpression of human tau in Hela cells.
• Analysis of secreted tau forms, including C-terminal cleavage.
• Assessment of tau phosphorylation status using phospho-dependent antibodies.
• Comparison of secretion levels for wild-type tau, hyperphosphorylated tau mimics, and a caspase-3 cleavage site mutant.

Main Results:

• Overexpressed human tau was secreted by Hela cells, primarily in a C-terminally cleaved form.
• Secreted tau was dephosphorylated compared to intracellular tau.
• Phosphorylation and C-terminal cleavage significantly enhanced tau secretion.
• A tau mutant truncated at the caspase-3 cleavage site (D421) showed increased secretion.

Conclusions:

• Hyperphosphorylation and cleavage of tau promote its secretion from cells.
• Tau secretion, influenced by phosphorylation and cleavage, may drive tau pathology propagation in Alzheimer's disease.
• These processes could explain the accumulation of tau in the cerebrospinal fluid of AD patients.