Hyperphosphorylation Renders Tau Prone to Aggregate and to Cause Cell Death

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Alzheimer's disease (AD) is a neurodegenerative disorder with no cure.
• Hyperphosphorylated tau forms neurofibrillary tangles (NFTs), correlating with cognitive decline.
• Understanding tau phosphorylation is crucial for AD drug development.

Purpose of the Study:

• To prepare and characterize recombinant hyperphosphorylated tau (p-tau) relevant to AD.
• To investigate the aggregation and cytotoxicity of this disease-relevant p-tau.
• To assess p-tau's potential as a tool for AD research and drug discovery.

Main Methods:

• Utilized the PIMAX approach to generate recombinant p-tau.
• Characterized p-tau phosphorylation at AD-relevant epitopes.
• Assessed p-tau aggregation, cytotoxicity, and seeding activity in cellular models.

Main Results:

• Generated p-tau phosphorylated at multiple AD-associated epitopes.
• p-tau formed fibrils without inducers, triggering mitochondrial superoxide and apoptosis.
• p-tau exhibited seeding activity, converting unmodified tau into a cytotoxic species.
• p-tau-induced apoptosis was mitigated by reactive oxygen species inhibitors.

Conclusions:

• Hyperphosphorylation drives tau into an aggregation-prone, cytotoxic conformation.
• p-tau mimics key pathological features of tauopathies like AD.
• This characterized p-tau is a valuable tool for AD mechanistic and drug discovery studies.