Japan has entered an era of population super-aging. According to estimates from the Ministry of Health, Labour and Welfare, approximately 5.23 million people in Japan will have dementia by 2030. When mild cognitive impairment (MCI) is included, the number is projected to reach approximately 11.16 million. By 2040, about one in three people aged 65 or older is estimated to have dementia or be at increased risk of developing it1. The social cost is also substantial. Medical costs, long-term care expenses, and informal care costs totaled an estimated ¥14.5 trillion per year in 2014 and are projected to rise to ¥24.3 trillion by 20602.
Alzheimer’s disease accounts for approximately 60–70% of dementia cases, yet no curative treatment has been established. Recently approved antibody drugs, including lecanemab, are designed to remove amyloid-β but do not completely stop disease progression. Researchers therefore continue to investigate whether intervention may be possible before symptoms emerge.
The study discussed here is preclinical research conducted in the context of ongoing treatment and prevention research. It examined how hexaraphane/6-MSITC, a compound found in Japanese wasabi, affected abnormal tau protein in a mouse model of Alzheimer’s disease.
What You Will Learn
- Cell and animal studies found that hexaraphane/6-MSITC reduced abnormal tau phosphorylation.
- The proposed mechanism was distinct from the established antioxidant NRF2 pathway and involved activation of PP2A, an enzyme that removes phosphate groups from tau.
- After oral administration in mice, hexaraphane/6-MSITC reached the brain and was associated with lower blood p-tau217 and improvements in cognitive and motor measures.
Background: Two Proteins Involved in Alzheimer’s Disease
The amyloid cascade hypothesis is one widely supported model of Alzheimer’s disease pathogenesis. According to this hypothesis, abnormalities in two proteins—amyloid-β and tau—initiate a chain of events that damages neurons.
Importantly, these pathological changes begin long before symptoms appear. Amyloid-β accumulation has been reported to begin approximately 20 years before disease onset, while tau abnormalities, or neurofibrillary changes, may begin approximately 10 years before onset. By the time a person notices memory problems, changes in the brain may already have been progressing for many years34.
How do these two proteins affect the brain?
Amyloid-β accumulation occurs first. In a healthy brain, amyloid-β can be broken down and cleared naturally. In Alzheimer’s disease, this clearance process becomes impaired, allowing amyloid-β to accumulate in plaque-like deposits known as senile plaques. Amyloid-β accumulation alone does not necessarily cause widespread neuronal injury. A key concern is that it may trigger abnormal changes in tau.
Amyloid-β accumulation is associated with excessive phosphorylation of tau protein. Tau normally helps stabilize microtubules, which form part of a neuron’s structural framework. When tau is excessively phosphorylated, it detaches from microtubules and forms abnormal intracellular aggregates called neurofibrillary tangles. Neurons containing these tangles lose function and eventually die. The brain consequently atrophies, with functional loss often beginning in the hippocampus, a region central to memory.
Tau Phosphorylation Is Regulated by an Accelerator and a Brake
Tau phosphorylation can be understood as a balance between an accelerator and a brake.
- Accelerators—kinases: Enzymes such as GSK-3β and CDK5 that attach phosphate groups to tau
- Brakes—phosphatases: Enzymes that remove phosphate groups from tau. Among them, PP2A accounts for approximately 70% of tau dephosphorylation in the brain, making it the principal brake5.
In a healthy brain, phosphorylation and dephosphorylation remain balanced. In the brains of people with Alzheimer’s disease, however, PP2A activity is reduced. As this braking function weakens, tau phosphorylation can proceed unchecked.
Much previous therapeutic research has focused on reducing the accelerator by inhibiting kinases that promote phosphorylation, but this strategy has not produced sufficient results. An alternative approach is therefore attracting attention: restoring the weakened brake.
Hexaraphane/6-MSITC as a Candidate for Restoring the Brake
Could any compound restore reduced PP2A activity? One candidate is hexaraphane/6-MSITC, a naturally occurring pungent compound in Japanese wasabi (Wasabia japonica). It belongs to a class of compounds known as isothiocyanates.
Previous studies have reported that hexaraphane/6-MSITC may have the following properties:
- Activation of the NRF2 pathway, which regulates cellular antioxidant and anti-inflammatory defenses
- Neuroprotective effects in animal studies
- Low toxicity, prompting interest in its safety profile
What Was Known—and What Was Not
Animal studies had previously reported that hexaraphane/6-MSITC affected amyloid-β accumulation in Alzheimer’s disease models through the NRF2 pathway6 7.
However, whether hexaraphane/6-MSITC could affect tau phosphorylation, another major component of Alzheimer’s disease pathology, had not been examined.
The new paper investigated this previously untested area.
What the Study Found
1. Cell Studies: Hexaraphane/6-MSITC Reduced Abnormal Tau Phosphorylation
In experiments using neurons from an Alzheimer’s disease mouse model, adding hexaraphane/6-MSITC produced dose-dependent reductions in AT8 and PHF1, markers of pathological tau phosphorylation.
Notably, cells lacking the antioxidant regulator NRF2 showed reductions in tau phosphorylation comparable to those observed in cells with NRF2. This finding suggests that the effect of hexaraphane/6-MSITC on tau phosphorylation occurred through an NRF2-independent mechanism.
Hexaraphane/6-MSITC dose and effects on tau-phosphorylation markers and antioxidant proteins. Source: García-Yagüe AJ et al., Redox Biology 92, 104107 (2026), adapted from Fig. 1B. How to read the figure: The four graphs measure different proteins. As the dose of hexaraphane/6-MSITC (HXN) increased, the antioxidant proteins NRF2 and HO-1 increased, while the pathological tau-phosphorylation markers PHF1 and AT8 declined in a dose-dependent manner.
2. Mechanism: Activation of the PP2A Brake
Through a series of experiments, the researchers found that:
- The effects of hexaraphane/6-MSITC could not be explained by inhibition of GSK-3β, the kinase previously considered the accelerator8.
- Instead, hexaraphane/6-MSITC increased the activity of PP2A, promoting tau dephosphorylation.
- When PP2A activity was experimentally blocked, the effect of hexaraphane/6-MSITC disappeared.
These findings indicate that hexaraphane/6-MSITC did not reduce tau abnormalities by easing the accelerator. Rather, it appeared to act through a distinct mechanism that strengthened the brake.
3. Hexaraphane/6-MSITC Reached the Brain After Oral Administration
The researchers measured compound concentrations in the brains of mice after oral administration of hexaraphane/6-MSITC.
- Neocortex: Peak concentration of approximately 20 ppb, reached within 30 minutes to 1 hour
- Brainstem: Peak concentration of 12–15 ppb, reached within 30 minutes to 1 hour
- Hippocampus: Peak concentration of 4–6 ppb, reached within 30 minutes to 1 hour
These measurements confirmed that orally administered hexaraphane/6-MSITC crossed the blood–brain barrier and reached the mouse brain. Although its residence time in the brain was relatively short—approximately 1–2 hours—the study suggested that repeated administration might produce biological effects.
4. Animal Studies: Tau Markers Changed in Both the Brain and Blood
After an Alzheimer’s disease mouse model received oral hexaraphane/6-MSITC for five weeks, the following changes were reported.
Tau-related changes:
- Markers of pathological tau phosphorylation declined in the neocortex, brainstem, and hippocampus.
- Blood p-tau217 also declined to a statistically significant degree. p-tau217 is being studied as a biomarker for the early detection of Alzheimer’s disease9.
Changes in blood p-tau217 concentrations before and after five weeks of hexaraphane/6-MSITC administration. Source: García-Yagüe AJ et al., Redox Biology 92, 104107 (2026), adapted from Fig. 6B. How to read the figure: The vertical axis shows p-tau217 concentration. Each point represents one mouse, with lines connecting measurements before and after treatment. In the hexaraphane/6-MSITC group, labeled 6-MSITC, many animals had lower values after treatment than before treatment.
Effects on neuroinflammation:
- In the neocortex and brainstem, inflammatory markers including COX2, IL-1β, and IL-6 declined.
- Astrocytes and microglia, glial cells involved in immune responses in the brain, tended to shift from an inflammation-associated activated state toward a resting state.
- The anti-inflammatory effect in the hippocampus was less pronounced than in the neocortex. The researchers suggested that one contributing factor may have been the hippocampal concentration of hexaraphane/6-MSITC, which was approximately one-quarter of that in the neocortex.
Neuronal integrity and amyloid pathology:
- Expression of calbindin D28k, a marker of neuronal integrity, was maintained.
- The number of amyloid-β plaques in the neocortex declined by approximately 50%.
5. Cognitive and Motor Measures
In an experiment involving 10-month-old model mice treated for six weeks, the following functional changes were reported:
- Memory test involving recognition of a novel object: The discrimination score increased by 2.0–2.5-fold.
- Treadmill test: Motor performance improved from week 3 and remained improved through week 5.
- Synaptic plasticity measured by hippocampal long-term potentiation: The efficiency of communication between neurons recovered.
Two Proposed Pathways of Hexaraphane/6-MSITC Action
Taken together, the findings suggest that hexaraphane/6-MSITC acts through two independent pathways.
- PP2A pathway, independent of NRF2: Activation of PP2A promotes tau dephosphorylation.
- NRF2 pathway: Activation of NRF2 strengthens cellular antioxidant and anti-inflammatory defenses.
The authors reported this as the first study in a tauopathy model to show reductions in both brain tau markers and blood p-tau217 together with improvements in cognitive and motor measures.
Remaining Questions
This was preclinical research conducted in mice. Further studies are needed before any effects in humans can be determined. The paper identified three major questions for future research:
- The study did not directly assess effects on tau aggregates.
- The molecular mechanism through which PP2A is activated remains unknown.
- Long-term safety assessment and clinical trials in humans are required.
Discussion: What This Study Adds
Drug-development research in Alzheimer’s disease has largely focused on removing amyloid-β or inhibiting kinases that accelerate tau phosphorylation. Only a limited number of these strategies have produced sufficient results in clinical trials. By proposing the activation of PP2A to restore braking function, this study explored a different direction that may broaden the range of research strategies.
The practical features of the study design are also notable. The researchers used a food-derived compound rather than a synthetic molecule, administered it orally, measured its arrival in the brain, and tracked effects with the blood biomarker p-tau217. Combining a food-derived compound, oral administration, and blood-biomarker monitoring could reduce some of the barriers to designing human clinical trials. p-tau217 is also increasingly being used as an outcome measure in trials of antibody drugs such as lecanemab, suggesting that the study could potentially use existing clinical assessment infrastructure.
Important limitations remain. A mouse brain weighs only approximately 0.04% as much as a human brain. It is unknown whether the hippocampal concentrations measured in this study—4–6 ppb—could be reproduced in the human brain. PP2A also functions broadly in organs outside the brain, so the risk of unintended effects from systemic activation requires investigation.
This is a single preclinical report. Nevertheless, with the social cost of dementia reaching tens of trillions of yen annually, expanding the range of research options remains important. The identification of a natural compound that may act through a different mechanism warrants further investigation, but it does not establish prevention or treatment of Alzheimer’s disease in humans.
References
- 厚生労働省「認知症及び軽度認知障害（MCI）の高齢者数と有病率の将来推計」（令和５年度 老人保健事業推進費等補助金、九州大学 二宮利治教授）2024年5月 ↩
- Sado M et al. "The estimated cost of dementia in Japan, the most aged society in the world." PLOS ONE 13(11): e0206508 (2018) ↩
- Jack CR Jr. et al. "Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade" Lancet Neurology 9(1): 119-128 (2010) ↩
- Bateman RJ et al. "Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease" New England Journal of Medicine 367: 795-804 (2012) ↩
- Qian W et al. "PP2A regulates tau phosphorylation directly and also indirectly via activating GSK-3beta" J Alzheimers Dis 19(4), 1221-1229 (2010) ↩
- Morroni F et al. "Protective effects of 6-(Methylsulfinyl)hexyl isothiocyanate on Aβ(1-42)-Induced cognitive deficit, oxidative stress, inflammation, and apoptosis in mice" Int J Mol Sci 19(7) (2018) ↩
- Uruno A et al. "Nrf2 suppresses oxidative stress and inflammation in App Knock-In Alzheimer's Disease model mice" Mol Cell Biol 40(6) (2020) ↩
- García-Yagüe AJ et al. "Dual targeting of Keap1 and Gsk-3 by hexaraphane in the regulation of transcription factor Nrf2" Free Radic Biol Med 239, 579-593 (2025) ↩
- 本論文 Discussion 内引用 ↩
