Dephosphorylated rather than hyperphosphorylated Tau triggers a pro-inflammatory profile in microglia through the p38...

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Tauopathies are neurodegenerative diseases defined by Tau protein aggregation.
• Neuroinflammation, involving microglia activation and pro-inflammatory molecules, is a key feature.
• Extracellular Tau promotes inflammation, but the precise mechanism is unclear.

Purpose of the Study:

• To investigate how extracellular Tau induces pro-inflammatory responses in microglia.
• To identify which forms of Tau trigger these responses.
• To elucidate the molecular pathways involved in Tau-mediated microglial activation.

Main Methods:

• Primary microglia cultures were treated with different forms of extracellular Tau.
• Analyzed pro-inflammatory responses using protein cytokine arrays and real-time PCR.
• Investigated the role of the p38 MAPK pathway and used phosphatase assays and immunoblotting.

Main Results:

• Extracellular non-phosphorylated and dephosphorylated Tau, not hyperphosphorylated Tau, activated the p38 MAPK pathway in microglia.
• This activation led to a pro-inflammatory response.
• The study identified specific Tau phosphorylation states as triggers for microglial activation.

Conclusions:

• Extracellular Tau, in specific dephosphorylated or non-phosphorylated states, directly activates microglia.
• The p38 MAPK pathway is a critical mediator of Tau-induced microglial pro-inflammatory responses.
• Understanding these mechanisms is crucial for developing targeted therapies for tauopathies.