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Et Tu, Methylene Blue? Drug Only Works as Prophylactic

methylene blue

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#1 axonopathy

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Posted 24 June 2015 - 09:26 PM


"According to the latest study on tau-transgenic mice, methylene blue, a drug in clinical trials for frontotemporal dementia (FTD) and Alzheimer's disease (AD), stops decline in its tracks—but only when given at the earliest stages. The report in the May 10 Acta Neuropathologica Communications comes from the lab of Eva-Maria and Eckhard Mandelkow at the German Center for Neurodegenerative Diseases (DZNE) in Bonn, Germany. They found that treating their own tau-transgenic mice up to three months before the onset of learning and memory impairments markedly improved their performance compared to untreated controls. However, the drug failed to rescue when given after deficits appeared. The data imply that methylene blue could work only as a preventative treatment in FTD and other tauopathies, including AD.

 

“It suggests that with methylene blue, you would have to treat early in patients who have Alzheimer’s,” said Eva-Maria Mandelkow, pointing to a need for better biomarkers that catch tau accumulation early. However, this proof-of-concept study also hints that a stronger anti-aggregation compound might treat later in the disease, she said. Alzforum briefly reported on some of these preliminary findings from the International Conference on Alzheimer’s Disease two years ago (seeMar 2013 news story).

 

Methylene blue is FDA-approved for a number of conditions (for review, see Schirmer et al., 2011). The compound crosses the blood-brain barrier, and reportedly prevents aggregation of a variety of neurodegenerative proteins, including tau, TDP-43, and huntingtin in vitro, and in cell and animal models (Wischik et al., 1996Arai et al., 2010Sontag et al., 2012).

 

It’s not clear how methylene blue works. Some scientists suggest it disrupts tau aggregation by oxidizing it and keeping it in monomer form (Feb 2013 news). Others say it stimulates protein degradation and reduces oxidative damage (Medina et al., 2011Congdon et al., 2012Stack et al., 2014). In 2008, Claude Wischik of TauRx Therapeutics in Aberdeen, U.K., presented a Phase 2 trial in which the derivative Rember TM reportedly slowed cognitive decline in people with mild to moderate AD (Aug 2008 news). The modified version LMT-X TM is in Phase 3 for the treatment of behavioral-variant frontotemporal degeneration and AD (Oct 2012 news).

 

In the current experiment, first authors Katja Hochgräfe and Astrid Sydow wondered how much tau could build up before methylene blue was no longer protective. Would it have to be given long before, shortly before, or even after tau accumulates and symptoms arise? They designed different treatment regimens for two mouse models. The TauΔK mouse expresses a full-length version of human tau, minus lysine 280, that is prone to aggregation, accumulates phosphorylated tau, and develops a learning/memory impairment around 12 months (Eckermann et al., 2007). The TauRDΔK mouse expresses only the ΔK280 repeat domain responsible for tau aggregation. This mouse develops neurofibrillary tangles, its neurons die, and learning and memory problems emerge at around 10 months.

 

In both models, the tau transgene can be turned off, and the mice learn normally again even if decline had already started (Sydow et al., 2011Van der Jeugd et al., 2012).

 

The researchers staggered the time when these mice began getting their daily dose of 20 mg/kg of methylene blue in drinking water. They used six to 11 mice per group, a mix of male and females. The TauΔK mice started as 1½-month-old pups, at 9 months of age (three months before learning problems began), or at 15 months (three months after). The TauRDΔK mice got the treatment starting either at 1½ months of age, or at 15 months, five months after their impairments emerged.

 

At the end of treatment, when mice were older than 15 months, the researchers compared learning and memory in the Morris water maze to that of untreated transgenic mice and wild-type littermates. They also evaluated general motor and exploration behavior within an open field test. Finally, they analyzed the mouse brains for levels of insoluble, phosphorylated, and misfolded tau, as well as levels of presynaptic and postsynaptic proteins. They also checked whether proteins involved in autophagy, ubiquitin-proteasome function, and oxidative stress rose above normal. All the experiments were carried out in blinded fashion."

 

Source: http://www.alzforum....ks-prophylactic

 

 


Edited by axonopathy, 24 June 2015 - 09:28 PM.

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