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 217 concentrations. These molecular changes were accompanied by attenuation of neuroinflammatory markers, preservation of neuronal integrity, restoration of synaptic plasticity, and improvements in cognitive and motor performance. Collectively, our findings identify HXN as a potent modulator of pathological TAU phosphorylation. These results support the development of HXN as a promising disease-modifying therapeutic strategy for AD and other TAU-driven neurodegenerative disorders. • Hexaraphane significantly reduces pathological TAU hyperphosphorylation in cellular and in vivo models. • Reduce-pTAU effect by hexaraphane occurs independently of NRF2 activity and is not mediated by GSK-3β inhibition. • PP2A activation is a key mechanism underlying hexaraphane-induced TAU dephosphorylation. • Chronic oral hexaraphane treatment lowers brain and circulating pTAU levels and attenuates neuroinflammation in APP/TAU mice. • Hexaraphane improves cognitive and motor performance, supporting its potential as a disease-modifying therapy for tauopathies.
García‐Yagüe et al. (Sun,) studied this question.