Cysteine-Independent Inhibition of Alzheimer's Disease-like Paired Helical Filament Assembly by Leuco-Methylthioninium (LMT)

Al-Hilaly, Youssra K.; Pollack, Saskia J; Rickard, Janet E.; Simpson, Michael; Raulin, Ana-Caroline; Baddeley, Thomas C.; Schellenberger, Pascale; Storey, John M. D.; Harrington, Charles R.; Wischik, Claude M.; Serpell, Louise C.

doi:10.1016/j.jmb.2018.08.010

Cited by 31 publications

(31 citation statements)

References 34 publications

(61 reference statements)

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“…The protein involved is TDP-43 in more than half of bvFTD cases, whereas in AD it is tau protein in the majority of cases, with an unknown contribution of cases with limbic TDP-43 pathology [66]. The estimated brain concentration of hydromethylthionine required for pharmacological activity (0.02-0.06 M) [49] is consistent with its activity as an inhibitor of both tau [27] and TDP-43 [65] aggregation [34] in vitro, and with the doses required for activity in a tau transgenic mouse model of bvFTD [31]. In addition to different clinical manifestations and response to symptomatic treatments, the underlying pathology affects different classes of brain cells with a different neuroanatomical distribution in AD and bvFTD [67][68][69].…”

Section: Discussionmentioning

confidence: 69%

“…We have retained the LMTM abbreviation in contexts that require technical discussion of the distinctive properties of LMT, but otherwise we now use the INN more generally. We have reported recently that LMT rather than MT + is the active species blocking tau aggregation in vitro and that it acts at a tau:LMT molar ratio of 1 : 0.1 [27]. Its site of action is within the proteolytically stable core tau unit of the tau aggregates found in both bvFTD and AD [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

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Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia

Shiells

Schelter

Bentham

et al. 2020

JAD

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia

Shiells

Schelter

Bentham

et al. 2020

JAD

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“…The brain: plasma ratio for LMTM also makes it possible to estimate the steady state concentrations of LMT in the brain as 6-16 ng/ml (0.021-0.056 M) corresponding to the range of 0.3-0.8 ng/ml in plasma. We have reported recently that LMT blocks tau aggregation in vitro at a tau:LMT molar ratio of 1 : 0.1 [21]. Therefore, the brain concentration of aggregated tau at which LMT could theoretically have activity is less than ∼0.6 nmol/g.…”

Section: Discussionmentioning

confidence: 95%

“…We have retained the LMTM abbreviation in the present paper as it facilitates technical discussion of the distinctive properties of LMT. LMT, and not MT + , is the active species that blocks tau aggregation in vitro acting at a tau:LMT molar ratio of 1 : 0.1 [21]. In earlier studies, the MT moiety was also found to reverse the proteolytic stability of tangle filaments isolated from AD brain tissues at a similar molar ratio [19,22].…”

Section: Introductionmentioning

confidence: 90%

“…It is therefore a potent tau aggregation inhibitor with a site of action within the proteolytically stable core tau unit of the tangle filament [23][24][25]. LMT also blocks tau aggregation in cell-based assays [19,21] and reduces tau aggregation pathology and associated behavioral deficits in tau transgenic mouse models in vivo at a dose of 9 mg/kg/day [26]. This corresponds approximately to a human dose of 8-16 mg/day in terms of plasma C max considering that the half-life in mice is 4 h compared with 37 h in elderly humans.…”

Section: Introductionmentioning

confidence: 99%

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Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease

Schelter

Shiells

Baddeley

et al. 2019

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Background: Although hydromethylthionine is a potent tau aggregation inhibitor, no difference was found in either of two Phase III trials in mild to moderate Alzheimer's disease (AD) comparing doses in the range 150-250 mg/day with 8 mg/day intended as a control. Objective: To determine how drug exposure is related to treatment response. Methods: A sensitive plasma assay for the drug was used in a population pharmacokinetic analysis of samples from 1,162 of the 1,686 patients who participated in either of the Phase III trials with available samples and efficacy outcome data. Results: There are steep concentration-response relationships for steady state plasma levels in the range 0.3-0.8 ng/ml at the 8 mg/day dose. Using a threshold based on the lower limit of quantitation of the assay on Day 1, there are highly significant differences in cognitive decline and brain atrophy in patients with above threshold plasma levels, both for monotherapy and add-on therapy, but with effect sizes reduced by half as add-on. Plasma concentrations in the range 4-21 ng/ml produced by the high doses are not associated with any additional benefit.

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Tau strains shape disease

2021

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Tauopathies consist of over 25 different neurodegenerative diseases that include argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick’s disease (PiD). Tauopathies are defined by brain accumulation of microtubule-associated protein tau in fibrillar aggregates, whose prevalence strongly correlates with dementia. Dominant mutations in tau cause neurodegenerative diseases, and most increase its aggregation propensity. Pathogenesis of tauopathies may involve pathological tau conformers that serve as templates to recruit native protein into growing assemblies and also move between brain cells to cause disease progression, similar to prions. Prions adopt pathological conformations, termed “strains,” that stably propagate in living systems, and create unique patterns of neuropathology. Data from multiple laboratories now suggest that tau acts as a prion. It propagates unique strains indefinitely in cultured cells, and when these are inoculated into mouse models, they create defined neuropathological patterns, which establish a direct link between conformation and disease. In humans, distinct fibril structures are associated with different diseases, but causality has not been established as in mice. Cryo-EM structures of tau fibrils isolated from tauopathy brains reveal distinct fibril cores across disease. Interestingly, the conformation of the tau monomer unit within different fibril subtypes from the same patient appears relatively preserved. This is consistent with data that the tau monomer samples an ensemble of conformations that act as distinct pathologic templates in the formation of restricted numbers of strains. The propensity of a tau monomer to adopt distinct conformations appears to be linked to defined local motifs that expose different patterns of amyloidogenic amino acid sequences. The prion hypothesis, which predicts that protein structure dictates resultant disease, has proved particularly useful to understand the diversity of human tauopathies. The challenge now is to develop methods to rapidly classify patients according to the structure of the underlying pathological protein assemblies to achieve more accurate diagnosis and effective therapy.

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Cysteine-Independent Inhibition of Alzheimer's Disease-like Paired Helical Filament Assembly by Leuco-Methylthioninium (LMT)

Cited by 31 publications

References 34 publications

Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia

Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia

Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease

Tau strains shape disease

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