Ca2+ and Mg2+ selectively induce aggregates of PHF-tau but not normal human tau

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Pathological aggregation of microtubule-associated protein tau (PHF-tau) is a hallmark of neurodegenerative diseases.
• The precise molecular mechanisms driving tau aggregation remain incompletely understood.

Purpose of the Study:

• To investigate the in vitro effects of various metal ions on the aggregation of normal and pathological tau proteins.
• To elucidate the role of specific metal ions in the formation of PHF-tau aggregates.

Main Methods:

• Utilized paired helical filament tau (PHF-tau) from Alzheimer's disease (AD) and corticobasal degeneration (CBD) brains, alongside normal human tau from fetal and adult brains and a recombinant system.
• Employed sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and immunoblotting to analyze protein aggregation and precipitation.
• Conducted intermixing experiments to determine the composition of induced aggregates.

Main Results:

• Calcium (Ca2+) and magnesium (Mg2+) ions specifically induced aggregation of PHF-tau, forming ~340 kD aggregates, but did not affect normal tau.
• Aluminum (Al3+) and iron (Fe2+) ions precipitated both PHF-tau and normal tau into SDS-insoluble pellets.
• Copper (Cu2+), zinc (Zn2+), and lithium (Li+) ions showed no effect on tau aggregation or precipitation.
• Ca2+-induced aggregates contained PHF-tau, excluding both unmodified recombinant and phosphorylated fetal tau, indicating the necessity of specific post-translational modifications.

Conclusions:

• Ca2+ and Mg2+ ions play a significant role in the aggregation of PHF-tau, distinct from their effect on normal tau.
• Post-translational modifications, beyond fetal-type phosphorylation, are crucial for Ca2+- and Mg2+-dependent PHF-tau aggregation.
• Elevated regional concentrations of Ca2+ and Mg2+ may act as triggers for pathological PHF-tau deposition in neurodegenerative disorders.