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

Shiells, Helen; Schelter, Björn; Bentham, Peter; Baddeley, Thomas C.; Rubino, Christopher M.; Ganesan, Harish; Hammel, Jeffrey; Vuksanovic, Vesna; Staff, Roger T.; Murray, Alison; Bracoud, Luc; Wischik, Damon; Riedel, Gernot; Gauthier, Serge; Jia, Jianping; Moebius, Hans J; Hardlund, Jiri; Kipps, Christopher; Kook, Karin A.; Storey, John M. D.; Harrington, Charles R.

doi:10.3233/jad-191173

Cited by 23 publications

(22 citation statements)

References 79 publications

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“…However, further studies showed that the lowest dose of LMTM (4 mg/kg twice daily), originally intended as a placebo, was as effective as the much higher dose (100 mg/kg twice daily) in slowing cognitive decline and brain atrophy in patients with AD [215,216]. Similar results were obtained in patients with frontotemporal dementia with behavioral variants (bvFTD) [217]. This improvement may be due to the complex effect of MB on tau aggregation in vivo and/or to other properties of the compound.…”

Section: Rescue From Tau Oligomers: Degradation or Polymerization?mentioning

confidence: 72%

Tau Oligomers Neurotoxicity

Niewiadomska

Niewiadomski

Steczkowska

et al. 2021

Life

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Although the mechanisms of toxic activity of tau are not fully recognized, it is supposed that the tau toxicity is related rather not to insoluble tau aggregates but to its intermediate forms. It seems that neurofibrillar tangles (NFTs) themselves, despite being composed of toxic tau, are probably neither necessary nor sufficient for tau-induced neuronal dysfunction and toxicity. Tau oligomers (TauOs) formed during the early stages of tau aggregation are the pathological forms that play a key role in eliciting the loss of neurons and behavioral impairments in several neurodegenerative disorders called tauopathies. They can be found in tauopathic diseases, the most common of which is Alzheimer’s disease (AD). Evidence of co-occurrence of b-amyloid, α-synuclein, and tau into their most toxic forms, i.e., oligomers, suggests that these species interact and influence each other’s aggregation in several tauopathies. The mechanism responsible for oligomeric tau neurotoxicity is a subject of intensive investigation. In this review, we summarize the most recent literature on the damaging effect of TauOs on the stability of the genome and the function of the nucleus, energy production and mitochondrial function, cell signaling and synaptic plasticity, the microtubule assembly, neuronal cytoskeleton and axonal transport, and the effectiveness of the protein degradation system.

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Section: Rescue From Tau Oligomers: Degradation or Polymerization?mentioning

confidence: 72%

Tau Oligomers Neurotoxicity

Niewiadomska

Niewiadomski

Steczkowska

et al. 2021

Life

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“…The deposition of aggregates of hyperphosphorylated tau protein constitutes the intracellular neurofibrillary tangles, a major histological evidence of AD. The role of tau hyperphosphorylation and aggregation in AD has established both of them as a target for therapeutic intervention [8], although only N,N,N',N'-tetramethyl-10H-phenothiazine-3,7-diaminium (TRX0237, leucomethylthioninium), the reduced form of methylene blue dye, acting as an inhibitor of tau aggregation, has reached the clinical phase III [26]. In recent years, some of us developed an efficient cell-based assay of tau aggregation, a simple and inexpensive method that provides a straightforward assay to evaluate the putative anti-aggregation capacity of small molecules [27][28][29].…”

Section: Cytoprotection From Tau Toxicitymentioning

confidence: 99%

Pharmacophore Modeling and 3D-QSAR Study of Indole and Isatin Derivatives as Antiamyloidogenic Agents Targeting Alzheimer’s Disease

et al. 2020

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Thirty-six novel indole-containing compounds, mainly 3-(2-phenylhydrazono) isatins and structurally related 1H-indole-3-carbaldehyde derivatives, were synthesized and assayed as inhibitors of beta amyloid (Aβ) aggregation, a hallmark of pathophysiology of Alzheimer’s disease. The newly synthesized molecules spanned their IC50 values from sub- to two-digit micromolar range, bearing further information into structure-activity relationships. Some of the new compounds showed interesting multitarget activity, by inhibiting monoamine oxidases A and B. A cell-based assay in tau overexpressing bacterial cells disclosed a promising additional activity of some derivatives against tau aggregation. The accumulated data of either about ninety published and thirty-six newly synthesized molecules were used to generate a pharmacophore hypothesis of antiamyloidogenic activity exerted in a wide range of potencies, satisfactorily discriminating the ‘active’ compounds from the ‘inactive’ (poorly active) ones. An atom-based 3D-QSAR model was also derived for about 80% of ‘active’ compounds, i.e., those achieving finite IC50 values lower than 100 μM. The 3D-QSAR model (encompassing 4 PLS factors), featuring acceptable predictive statistics either in the training set (n = 45, q2 = 0.596) and in the external test set (n = 14, r2ext = 0.695), usefully complemented the pharmacophore model by identifying the physicochemical features mainly correlated with the Aβ anti-aggregating potency of the indole and isatin derivatives studied herein.

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“…Interestingly, LMTM was found to have an almost identical exposure-response profile in a large Phase 3 clinical trial of bvFTD as that seen for AD ( 272 ). Fewer than half of bvFTD patients have tau aggregation pathology, with the remainder exhibiting pathological aggregation of TAR DNA binding protein 43, TDP-43.…”

Section: Alzheimer's Disease Therapies Targeting Tau Self-assemblymentioning

confidence: 95%

Tau Filament Self-Assembly and Structure: Tau as a Therapeutic Target

et al. 2020

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Tau plays an important pathological role in a group of neurodegenerative diseases called tauopathies, including Alzheimer's disease, Pick's disease, chronic traumatic encephalopathy and corticobasal degeneration. In each disease, tau self-assembles abnormally to form filaments that deposit in the brain. Tau is a natively unfolded protein that can adopt distinct structures in different pathological disorders. Cryo-electron microscopy has recently provided a series of structures for the core of the filaments purified from brain tissue from patients with different tauopathies and revealed that they share a common core region, while differing in their specific conformation. This structurally resolvable part of the core is contained within a proteolytically stable core region from the repeat domain initially isolated from AD tau filaments. Tau has recently become an important target for therapy. Recent work has suggested that the prevention of tau self-assembly may be effective in slowing the progression of Alzheimer's disease and other tauopathies. Here we review the work that explores the importance of tau filament structures and tau self-assembly mechanisms, as well as examining model systems that permit the exploration of the mode of action of potential inhibitors.

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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

Abstract: Background: Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins. Objective: To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD.

Cited by 23 publications

References 79 publications

Tau Oligomers Neurotoxicity

Tau Oligomers Neurotoxicity

Pharmacophore Modeling and 3D-QSAR Study of Indole and Isatin Derivatives as Antiamyloidogenic Agents Targeting Alzheimer’s Disease

Tau Filament Self-Assembly and Structure: Tau as a Therapeutic Target

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