Hexaraphane as a potential therapeutic strategy for tauopathies

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Alzheimer's disease (AD) involves TAU protein hyperphosphorylation, leading to neurodegeneration.
• Hexaraphane (HXN), a Wasabia japonica compound, has known neuroprotective effects, but its role in TAU pathology was unexplored.

Purpose of the Study:

• To investigate HXN's effect on pathological TAU phosphorylation.
• To elucidate the underlying molecular mechanisms of HXN's action in vitro and in vivo.

Main Methods:

• Primary neurons from APP/TAU transgenic mice (NRF2 wild-type and knockout) were used.
• Genetic and pharmacological approaches, including phosphatase assays, were employed.
• Chronic oral administration of HXN in APP/TAU mice was performed.

Main Results:

• HXN significantly reduced pathological TAU epitopes (AT8, PHF1) independently of NRF2.
• HXN promotes TAU dephosphorylation via PP2A activation, not by inhibiting GSK-3β or altering PI3K/AKT/MAPK pathways.
• In vivo, HXN decreased brain and blood phospho-TAU levels, attenuated neuroinflammation, preserved neurons, and improved cognition and motor function.

Conclusions:

• HXN is a potent modulator of pathological TAU phosphorylation through PP2A activation.
• HXN demonstrates disease-modifying potential for Alzheimer's disease and other TAU-driven neurodegenerative disorders.