Fyn Kinase Controls Tau Aggregation In Vivo

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Alzheimer's disease (AD) involves amyloid-beta (Aβ) plaques and tau neurofibrillary tangles (NFTs).
• Fyn kinase mediates Aβ toxicity in a tau-dependent manner.
• The role of Fyn in tau pathology without Aβ is unknown.

Purpose of the Study:

• To investigate the role of Fyn kinase in tau pathology independent of Aβ.
• To determine if Fyn inhibition can reduce tau pathology in a model lacking Aβ.

Main Methods:

• Generation of a transgenic mouse model (Tg/Fyn-/-) overexpressing mutant tau with Fyn kinase knockout.
• Analysis of neurofibrillary tangle formation, tau hyperphosphorylation, solubility, and synaptic accumulation.
• Assessment of tau seeding potential in tau biosensor cells.
• In vitro investigation of tau fibrillization influenced by Fyn-mediated phosphorylation.

Main Results:

• Tg/Fyn-/- mice showed near-complete ablation of NFTs and reduced tau hyperphosphorylation.
• Synaptic tau accumulation and altered tau solubility were diminished.
• Tau seeding activity in brain lysates was significantly reduced.
• Tau pseudophosphorylation at the Fyn epitope Y18 enhanced tau fibrillization.

Conclusions:

• Fyn kinase is a critical regulator of tau pathology, independent of Aβ.
• Targeting Fyn kinase may offer a therapeutic strategy for Alzheimer's disease and tauopathies.
• Fyn-mediated phosphorylation of tau is a key mechanism driving pathology.