Hydromethylthionine sustains truncated tau‐dependent inflammation‐lowering effects in mouse brain

Tauopathies are a heterogeneous mixture of neurodegenerative disorders, including Alzheimer's disease and frontotemporal dementia (FTD), characterised by the accumulation of tau filaments in brain tissue. Tau protein aggregation is inhibited by hydromethylthionine (HMT), an effect that appeared to be prevented in clinical trials for subjects already receiving acetylcholinesterase inhibitors or memantine. Since neuroinflammatory responses are associated with tauopathies, we investigated the effect of HMT on the brain immune response and inflammatory status in line 66 (L66) mice, an FTD-like model overexpressing human tau, in the presence of memantine. We determined whether HMT (5 and 15 mg·kg−1), either singly or combined with memantine (20 mg·kg−1), would have a sustained impact on neuroinflammation following the cessation of drug administration. The levels of core tau fragments in L66+/− mice (P301S/G335D-hTau) were decreased in a dose-dependent manner 12 weeks after the last administration of HMT, an effect that was not affected by memantine. HMT lowered the levels of tumour necrosis factor alpha (TNF-α), thus favouring an environment conducive to neuronal protection and repair. HMT sustained increased microglial reactivity after its discontinuation, which may assist in the removal of tau aggregates, but co-administration with memantine prevented the HMT-sustained activation of microglia. These findings indicate that HMT has a beneficial effect in reducing neuroinflammation that accompanies a decrease in the accumulation of truncated tau species and that these benefits are not susceptible to interference by memantine. In turn, the nature of drug interference between HMT and memantine seems to be independent of tau and related to microglia reactivity.