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- Tau Busters -


General Information:

Names:
Wikipedia entry:
Dr. Ray Shahelien entry: 

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Observations:

See also Cinnamon
         Methylene Blue
         Niacinamide
         Grape seed extract
         Davunitide
         Nypta
         Valproic Acid
         Tau
         Metformin
         Epothilone D

Discovery Of Molecular Cause Of Alzheimer's Disease Could Bring Early Diagnosis, Treatment Closer
25 May 2009
... The crucial protein, called a tau protein, is a normal part of the brain and central nervous system. But in Alzheimer's patients, tau proteins go out of control and form tangles that, along with senile plaques, are the primary cause of the degenerative disease.

Several years ago, it was discovered that tau proteins in normal brains contain only three to four attached phosphates, while abnormal tau in Alzheimer's patients have anywhere from 21 to 25 additional phosphates...
http://www.medicalnewstoday.com/articles/151234.php


There are several substances we have heard about since late 2007 that might be tau busters. Here they are in the order I found out about them::
1.  Cinnamon Proanthocyanidins
2.  Methylene Blue (Rember)
3.  Niacinamide (Nicotinamide)
4.  Grape Seed Extract
5.  Davunetide
6.  Nypta
7.  Valproic Acid (VPA, Depakote)
8.  Metformin
9.  Epothilone D


The wording describing the action of the first six of these is almost identical: "capable of inhibiting tau peptide aggregations, as well as dissociating preformed tau peptide aggregates".

GSK-3 inhibitor drugs lithium and "NP-12" (Noscira, Spain), may also prevent tau protein corruption.  Lithium has side effects that make it difficult to use.  Clinical trials of NP-12 are ongoing (as of 3/6/2010).  In the clinical trials, the drug is referred to as "NP031112"  NP-12 is the commonly used name for NP031112. The drug is also known as Nypta®. The active ingredient is 4-benzyl-2-naphtalen-1-yl-1,2,4-thiadiazolidine-3,5-dione.

Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden

It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function.

Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection.

Results: Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, RemberTM, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced.

Conclusions: Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model.

Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced.

Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet"because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels.

This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.

Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden.
Author: John O'LearyQingyou LiPaul MarinecLaura BlairErin CongdonAmelia JohnsonUmesh JinwalJohn KorenJeffrey JonesClara KraftMelinda PetersJose AbisambraKaren DuffEdwin WeeberJason GestwickiChad Dickey
Credits/Source: Molecular Neurodegeneration 2010
http://7thspace.com/headlines/362179/phenothiazine_mediated_rescue_of_cognition_in_tau_transgenic_mice_requires_neuroprotection_and_reduced_soluble_tau_burden_.html
PMID: 21040568 [PubMed]PMCID: PMC2989315
http://www.ncbi.nlm.nih.gov/pubmed/21040568

Full text of the article:
Molecular Neurodegeneration 2010, 5:45doi:10.1186/1750-1326-5-45
http://www.molecularneurodegeneration.com/content/5/1/45

Pub Med Central:  PMCID: PMC2989315
Mol Neurodegener. 2010; 5: 45.
Published online 2010 November 1. doi: 10.1186/1750-1326-5-45.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989315/?tool=pubmed


On page 11 of the article, it says "A treatment of 650mg/day in a 70kg (154lb) human equates to 9.3mg/kg/day." So, 650mg spread through the day. However, on Page 2 it says that FDA guidelines are 10mg/kg (of body mass) for a mouse is equivalent to ~1mg/kg for a human. This seems to be a contradiction. I'm not sure where they got that 650mg number from. In the article it mentions that they were using 5 times the recommended dose. I don't know where they got the "recommended dose" from. It might be that they are using this 10:1 mouse to man ratio. It probably should have been 65mg/day dose for a 70kg human is about 1mg/kg. Then multiply by 10. The equivalent for a mouse would be about 10mg/day for a mouse. But a short cut to get that number would be to multiply the human dose by 10 and then divide by the weight of 70kg. If this is so, 65mg isn't so bad. If I remember correctly, the clinical trials of Rember (a variation on the methylene blue theme) used something like 60mg 3 times per day. There is a post about it on the group's Yahoo web site about 2 years ago.

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Known sources:


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Natural sources:


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References:


Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden.
O'Leary JC 3rd, Li Q, Marinec P, Blair LJ, Congdon EE, Johnson AG, Jinwal UK, Koren J 3rd, Jones JR, Kraft C, Peters M, Abisambra JF, Duff KE, Weeber EJ, Gestwicki JE, Dickey CA.
Mol Neurodegener. 2010 Nov 1;5:45.Source
Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, FL 33613, USA. cdickey@health.usf.edu.
Abstract
BACKGROUND:

It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection.
RESULTS:

Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember™, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced.
CONCLUSIONS:

Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.

PMID:  21040568  [PubMed] PMCID:  PMC2989315
http://www.ncbi.nlm.nih.gov/pubmed/21040568
Full Text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989315/?tool=pubmed

 The characterization of microtubule-stabilizing drugs as possible therapeutic agents for Alzheimer's disease and related tauopathies.
Brunden KR, Yao Y, Potuzak JS, Ferrer NI, Ballatore C, James MJ, Hogan AM, Trojanowski JQ, Smith AB 3rd, Lee VM.
Pharmacol Res. 2011 Apr;63(4):341-51. Epub 2010 Dec 14.
Source: Center for Neurodegenerative Disease Research and Institute on Aging, Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States. kbrunden@upenn.edu
Abstract
Tau, a protein that is enriched in neurons of the central nervous system (CNS), is thought to play a critical role in the stabilization of microtubules (MTs). Several neurodegenerative disorders referred to as tauopathies, including Alzheimer's disease and certain types of frontotemporal lobar degeneration, are characterized by the intracellular accumulation of hyperphosphorylated tau fibrils. Tau deposition into insoluble aggregates is believed to result in a loss of tau function that leads to MT destabilization, and this could cause neurodegeneration as intact MTs are required for axonal transport and normal neuron function. This tau loss-of-function hypothesis has been validated in a tau transgenic mouse model with spinal cord tau inclusions, where the MT-stabilizing agent, paclitaxel, increased spinal nerve MT density and improved motor function after drug absorption at neuromuscular junctions. Unfortunately, paclitaxel is a P-glycoprotein substrate and has poor blood-brain barrier permeability, making it unsuitable for the treatment of human tauopathies. We therefore examined several MT-stabilizing compounds from the taxane and epothilone natural product families to assess their membrane permeability and to determine whether they act as substrates or inhibitors of P-glycoprotein. Moreover, we compared brain and plasma levels of the compounds after administration to mice. Finally, we assessed whether brain-penetrant compounds could stabilize mouse CNS MTs. We found that several epothilones have significantly greater brain penetration than the taxanes. Furthermore, certain epothilones cause an increase in CNS MT stabilization, with epothilone D demonstrating a favorable pharmacokinetic and pharmacodynamic profile which suggests this agent merits further study as a potential tauopathy drug candidate.
PMID: 21163349 [PubMed] PMCID: PMC3042036
http://www.ncbi.nlm.nih.gov/pubmed/21163349
Full Text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3042036/?tool=pubmed



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Updated: July 2, 2012
Inception: July 2, 2012