Hexaraphane as a potential therapeutic strategy for tauopathies.

Alzheimer's disease (AD) is characterized by pathological hyperphosphorylation of TAU protein, leading to neurofibrillary tangle formation, synaptic dysfunction, neuroinflammation, and neuronal loss. Hexaraphane (6-(methylsulfinyl) hexyl isothiocyanate; HXN), a bioactive compound derived from Wasabia japonica, exhibits neuroprotective and anti-inflammatory properties, yet its potential role in tauopathies remains unknown. Here, we investigated whether HXN modulates pathological TAU phosphorylation and explored the underlying mechanisms in vitro and in vivo. Using primary neurons from APP/TAU transgenic mice with either NRF2 wild-type or knockout backgrounds, combined with complementary genetic and pharmacological approaches, we found that HXN markedly reduced pathological phospho-TAU epitopes (AT8 and PHF1). Notably, this effect occurred independently of NRF2 signaling. Mechanistically, HXN did not suppress GSK-3β activity or alter upstream PI3K/AKT or MAPK pathways. Instead, pharmacological inhibition experiments and phosphatase assays demonstrated that HXN promotes PP2A-dependent TAU dephosphorylation, identifying phosphatase activation as a central mechanism of action. Chronic oral administration of HXN in APP/TAU mice led to significant reductions in brain phospho-TAU levels across multiple regions and decreased blood circulating TAU-pThr