Fyn depletion ameliorates tau^P301L-induced neuropathology

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• The Src family kinase Fyn is linked to Alzheimer's disease via amyloid-beta interactions.
• Its role in primary tauopathies, such as Frontotemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP-17), is unclear.
• FTDP-17 is characterized by tau pathology in the absence of amyloid plaques.

Purpose of the Study:

• To investigate the role of Fyn in the pathogenesis of primary tauopathies.
• To determine if Fyn contributes to tau pathology and neurodegeneration in FTDP-17 models.

Main Methods:

• Adeno-associated virus serotype 8 (AAV2/8) vectors were used to deliver tau P301L mutation into wild-type (WT) and Fyn knockout (KO) mice brains.
• Generated somatic transgenic tauopathy models with and without Fyn.
• Assessed tau pathology using Bielschowsky and Thioflavin S staining.
• Measured levels of phosphorylated tau and synaptic proteins.
• Evaluated behavioral abnormalities.

Main Results:

• Both WT and Fyn KO mice developed tau pathology.
• Fyn KO mice exhibited reduced neurofibrillary tangles and lower levels of phosphorylated tau.
• Tau P301L-induced behavioral deficits and synaptic protein depletion were absent in Fyn KO mice.
• Fyn deficiency mitigated tauopathy progression and associated neurological impairments.

Conclusions:

• Fyn kinase is a critical factor in the disease pathogenesis of FTDP-17.
• Targeting Fyn may offer a therapeutic strategy for tauopathies.
• This study highlights Fyn's distinct role in tauopathies independent of amyloid pathology.