ArticleThe Journal of biological chemistry2015
Cellular Models of Aggregation-dependent Template-directed Proteolysis to Characterize Tau Aggregation Inhibitors for Treatment of Alzheimer Disease.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
58 citing papers in PubMed, 103 citations in OpenAlex.
- Clinical, imaging and blood biomarker outcomes in a Phase 3 clinical trial of tau aggregation inhibitor hydromethylthionine mesylate in mild cognitive impairment and mild to moderate dementia due to Alzheimer's disease.The journal of prevention of Alzheimer's disease · 2026Trial
- Oral Tau Aggregation Inhibitor for Alzheimer's Disease: Design, Progress and Basis for Selection of the 16 mg/day Dose in a Phase 3, Randomized, Placebo-Controlled Trial of Hydromethylthionine Mesylate.The journal of prevention of Alzheimer's disease · 2022Trial
- Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia.Journal of Alzheimer's disease : JAD · 2020Trial
- Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer's Disease.Journal of Alzheimer's disease : JAD · 2019Trial
- Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer's Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial.Journal of Alzheimer's disease : JAD · 2018Trial
- Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial.Lancet (London, England) · 2016Trial
- Atypical population pharmacokinetics of hydromethylthionine in patients with Alzheimer's disease explains unexpected phase 3 trial results.British journal of clinical pharmacology · 2026Article
- Review
- Cholesterol at the Center of Alzheimer's Disease: A Unifying Hypothesis on the Pathogenic Mechanism.Molecules (Basel, Switzerland) · 2026Review
- Assessment of clinical and neuroimaging efficacy of treatment targeting tau pathology in mild cognitive impairment and mild to moderate Alzheimer's disease with hydromethylthionine mesylate using external control data.The journal of prevention of Alzheimer's disease · 2026Article
- Tau Protein Aggregation Inhibitors-Therapeutic Strategy for Concurrent Tau and Amyloid Aggregation Inhibition.Biomedicines · 2026Review
- Targeting tau in Alzheimer's Disease: rationale, approach and challenges.Molecular neurodegeneration · 2026Review
- Pathological Disulfide Bond Crosslinking: Molecular Insights into Amyloidogenesis and Diseases Progression.Chembiochem : a European journal of chemical biology · 2025Review
- Pathological mechanisms and treatment progression of Alzheimer's disease.European journal of medical research · 2025Review
- Interplay Between Aging and Tau Pathology in Alzheimer's Disease: Mechanisms and Translational Perspectives.Antioxidants (Basel, Switzerland) · 2025Review
- Hydromethylthionine sustains truncated tau-dependent inflammation-lowering effects in mouse brain.The FEBS journal · 2025Article
- Tau is a receptor with low affinity for glucocorticoids and is required for glucocorticoid-induced bone loss.Cell research · 2025Article
- Pharmacotherapies for the Treatment of Progressive Supranuclear Palsy: A Narrative Review.Neurology and therapy · 2024Review
- Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review.Molecules (Basel, Switzerland) · 2024Review
- Article
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Authors and funding
15 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Alzheimer disease (AD) is a degenerative tauopathy characterized by aggregation of Tau protein through the repeat domain to form intraneuronal paired helical filaments (PHFs). We report two cell models in which we control the inherent toxicity of the core Tau fragment. These models demonstrate the properties of prion-like recruitment of full-length Tau into an aggregation pathway in which template-directed, endogenous truncation propagates aggregation through the core Tau binding domain. We use these in combination with dissolution of native PHFs to quantify the activity of Tau aggregation inhibitors (TAIs). We report the synthesis of novel stable crystalline leucomethylthioninium salts (LMTX®), which overcome the pharmacokinetic limitations of methylthioninium chloride. LMTX®, as either a dihydromesylate or a dihydrobromide salt, retains TAI activity in vitro and disrupts PHFs isolated from AD brain tissues at 0.16 μM. The Ki value for intracellular TAI activity, which we have been able to determine for the first time, is 0.12 μM. These values are close to the steady state trough brain concentration of methylthioninium ion (0.18 μM) that is required to arrest progression of AD on clinical and imaging end points and the minimum brain concentration (0.13 μM) required to reverse behavioral deficits and pathology in Tau transgenic mice.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.