Travels with tau prions

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Tau protein, identified as a microtubule-associated protein, forms pathological aggregates in Alzheimer disease and related tauopathies.
• Mutations in the MAPT gene linked to inherited tauopathies suggest tau aggregation is central to disease pathogenesis.
• Recent findings propose tau functions as a prion, forming self-propagating intracellular assemblies.

Purpose of the Study:

• To investigate the prion-like behavior of tau protein.
• To characterize the formation, propagation, and cellular entry mechanisms of tau aggregates (strains).
• To explore the implications of tau prion biology for understanding and treating tauopathies.

Main Methods:

• Utilizing simple cell culture systems to study tau aggregate formation and propagation.
• Employing mouse models to assess the neuropathological phenotypes induced by different tau strains.
• Investigating cellular uptake mechanisms, including heparan sulfate proteoglycan binding and macropinocytosis.
• Examining the role of valosin-containing protein in tau replication within the cytoplasm.

Main Results:

• Tau forms distinct, stably propagating aggregate conformations (strains) in simple cells.
• Each tau strain induces unique and transmissible neuropathological phenotypes in mice.
• Tau assemblies enter cells via macropinocytosis after binding to cell surface proteoglycans.
• Cytoplasmic entry and processing by valosin-containing protein are crucial for tau replication.
• Stable monomers represent the smallest seeding unit, indicating early folding events are critical.

Conclusions:

• Tau protein exhibits prion-like characteristics, with distinct strains driving tauopathy pathogenesis.
• Understanding tau prion replication and propagation offers insights into neurodegenerative disease mechanisms.
• Targeting tau prion formation and spread presents a potential therapeutic strategy for tauopathies.