Given the urgent need for a disease modifying treatment of Alzheimer’s disease (AD), there is increasing interest in tau‑based therapeutics. In a comparative study, methylthioninium chloride (MTC) and leucomethylthioninium salts (LMTX®) (5‑75 mg/kg; oral administration for 3-8 weeks) were assessed preclinically in two novel transgenic tau mouse lines (Line 1, Line 66). Behavioural and histopathological proxies were evaluated. Both MTC and LMTX® dose-dependently rescued the learning impairment and restored behavioural flexibility in a spatial problem‑solving water maze task in Line1 and corrected motor‑learning in Line 66. Simultaneously, both drugs reduced the number of tau-reactive neurons, particularly in the hippocampus and entorhinal cortex in Line 1 and had more widespread effects in Line 66. The data establish that diaminophenothiazine compounds like MTC can reverse both spatial and motor learning deficits and reduce the underlying tau pathology and therefore offer potential for the treatment of tauopathies. In the clinic, symptomatic treatments with cholinesterase inhibitors and/or memantine are relatively ineffective and the need for new treatments targeting the underlying pathology of AD is generally recognised. In most of the failed disease-modifying trials conducted over the last 16 years, patients have been allowed to continue taking symptomatic treatments at stable doses, under the assumption that they do not impair efficacy because the modes of action are different. In recently completed Phase 3 trials testing the tau aggregation inhibitor leuco-methylthioninium bis (hydromethanesulfonate) (LMTM), we found highly significant differences in treatment response according to whether patients were taking LMTM as monotherapy (benefit) or as add‑on to symptomatic treatments (no effect). A large body of preclinical research has then been undertaken in wild-type mice and in our tau transgenic mouse model (Line 1) expressing the core tau unit of the AD paired helical filament with the aim of understanding the mechanisms responsible for the reduced efficacy of LMTM as an add‑on to symptomatic treatments. A range of experimental paradigms were used to measure the effects of chronic pretreatment with the cholinesterase inhibitor rivastigmine given for 2-5 weeks prior to adding LMTM treatment for a further 2‑6 weeks. In tau transgenic mice, LMTM given alone was found to increase hippocampal acetylcholine (ACh) levels, glutamate release from synaptosomal preparations, synaptophysin levels in multiple brain regions, mitochondrial complex IV activity, reduce tau pathology, restore choline acetyl transferase (ChAT) immunoreactivity in basal forebrain, and reverse deficits in spatial learning. Chronic pretreatment with rivastigmine was found to reduce or eliminate almost all LMTM treatment effects, apart from reduction in tau aggregation pathology and restoration of ChAT immunoreactivity in the basal forebrain. LMTM effects on hippocampal ACh and levels of synaptophysin were also reversed in wild‑type mice. Collectively, targeting tangles consisting of MAPT protein tau is a viable strategy in preclinical models and was forward translated to AD patients receiving monotherapy. In the clinic, however, prior symptomatic treatment with a cholinesterase inhibitor prohibited the efficacy of LMTM. Back translation to our tau mouse model reproduced this negative interaction and revealed a mechanistic action across different transmitter systems and at multiple compartmental levels of neural function.
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