Tau-tubulin kinase

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Tau-tubulin kinase (TTBK) is a casein kinase superfamily member phosphorylating tau and tubulin.
• TTBK1, CNS-specific, phosphorylates tau and activates Cdk5; TTBK2 is ubiquitously expressed.
• Elevated TTBK1 and its gene variations link to Alzheimer's disease (AD) and tauopathy.

Purpose of the Study:

• Investigate TTBK1's role in neuroinflammation and neurodegeneration in tauopathy models.
• Elucidate TTBK1's mechanism in microglial activation and axonal injury.

Main Methods:

• Utilized TTBK1 transgenic mice crossed with tau mutant mice (P301L).
• Analyzed mononuclear phagocyte phenotypes in the spinal cord.
• Assessed microglial activation (M1/M2) and peripheral monocyte infiltration.
• Evaluated axonal degeneration in vitro upon TTBK1 overexpression.

Main Results:

• TTBK1 overexpression shifted spinal cord microglia from M2 to M1 phenotype, increasing pro-inflammatory peripheral monocytes.
• TTBK1 mediates M1-activated microglia-induced neurotoxicity.
• TTBK1 overexpression caused axonal degeneration in vitro.
• TTBK1 transgenic mice crossed with tau mutant mice showed tau accumulation, neuroinflammation, and neurodegeneration.

Conclusions:

• TTBK1 is a key mediator of inflammatory axonal degeneration in tauopathies.
• TTBK1 contributes significantly to Alzheimer's disease and other tau-related neurodegenerative pathobiology.