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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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May 30, 2013

Update on Bexarotene for Alzheimer's

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Posted by Derek

Here's a follow-up on the news that bexarotene might be useful for Alzheimer's. Unfortunately, what seems to be happening is what happens almost every time that the word "Alzheimer's" is mentioned along with a small molecule. As Nature reports here, further studies are delivering puzzling results.

The original work, from the Landreth lab at Case Western, reported lower concentrations of soluble amyloid, memory improvements in impaired rodents, and (quite strikingly), clearance of large amounts of existing amyloid plaque in their brain tissue. Now four separate studies (1, 2, 3, 4) are out in the May 24th issue of Science, and the waters are well muddied. No one has seen the plaque clearance, for one thing. Two groups have noted a lowering of soluble amyloid, though, and one study does report some effects on memory in a mouse model.

So where are we? Here's Landreth himself on the results:

It was our expectation other people would be able to repeat this,” says Landreth about the results of the studies. “Turns out that wasn’t the case, and we fundamentally don’t understand that.” He suggests that the other groups might have used different drug preparations that altered the concentration of bexarotene in the brain or even changed its biological activity.

In a response published alongside the comment articles, Landreth emphasizes that some of the studies affirm two key conclusions of the original paper: the lowering of soluble β-amyloid levels and the reversal of cognitive deficits. He says that the interest in plaques may even be irrelevant to Alzheimer’s disease.

That last line of thought is a bit dangerous. It was, after all, the plaque clearance that got this work all the attention in the first place, so to claim that it might not be that big a deal once it failed to repeat looks like an exercise in goalpost-shifting. There might be something here, don't get me wrong. But chasing it down is going to be a long-term effort. It helps, of course, that bexarotene has already been out in clinical practice for a good while, so we already know a lot about it (and the barriers to its use are lower). But there's no guarantee that it's the optimum compound for whatever this effect is. We're in for a long haul. With Alzheimer's, we're always in for a long haul, it seems. I wish it weren't so.

Comments (15) + TrackBacks (0) | Category: Alzheimer's Disease


COMMENTS

1. Electrochemist on May 30, 2013 8:58 AM writes...

Not sure I would characterize this as goalpost- shifting at all. In fact, a consistent theme seems to be emerging: some of these bexarotene studies appear to support earlier work suggesting that the N-terminus of soluble beta-amyloid protein is the species that damages the hippocampus, and that the presence of plaque is not strongly correlated with cognitive decline (G.M.Shankar and D.M.Walsh, Mol. Neurodegener.,4: 48, 2009).

Permalink to Comment

2. sepisp on May 30, 2013 10:12 AM writes...

Well, if you look at the molecule, a damn plank of axle grease with an carboxylic acid dongle, then I would certainly believe claims that absorption might be the problem, and that it could be reduced with the wrong method of administration.

Permalink to Comment

3. Matt on May 30, 2013 4:09 PM writes...

Or, it may be not so much goalpost-shifting as recognizing that the goalposts have been shifted, perhaps in the authors' favor. Haven't several of the amyloid antibody trials shown good clearance of plaque, to no significant cognitive effect? And hasn't the oligomeric form been implicated in a lot of the toxicity effects of amyloid beta?

Maybe the dramatic plaque clearance is what caught people's eye at first, but it seems silly to attach a hypothetical explanation for a drug's benefit and a hypothetical explanation for a disease's cause, and then discard the drug because its hypothetical explanation does not match the disease's hypothetical cause. Oh wait, we do that all the time. That's why phenotypic screens can have such power: they skip most of the bulls...poor explanations. It's generally best not to build your house of cards directly on piles of bullshit.

Going back to some of the first comments made on this topic: somebody ought to do a study on bexarotene patients, and look to see if some effect is plausibly there. The problem may be that no patient takes it long enough, or survives long enough, to make any difference for AD. And many cancer patients who are believed to be suffering from Alzheimer's may choose hospice care rather than aggressive treatment of the cancer.

From what I've read, bexarotene has nasty enough side effects that might force climbing out onto that hypothetical method-of-action limb, to find some other compound with similar action but less toxicity.

Permalink to Comment

4. Lane Simonian on May 30, 2013 4:50 PM writes...

Any compound that solely reduces either amyloid plaque or soluble amyloid oligomers will not effectively treat Alzheimer's disease, because amyloid only is a minor contributor to the main cause of the disease: peroxynitrites.

Peroxynitrites nitrate amyloid causing its aggregation, contriubte to the hyperphosphorlation and nitration of tau proteins, and the nitration of NMDA receptors. The latter is the most important because it results in the efflux of glutamate and the influx of calcium which kills brain cells.

Peroxynitrites also oxidize a whole series of g- protein coupled receptors including those involved in short-term memory (muscarinic acetylcholine), sleep (melatonin), mood (serotonin), smell (olfactory), alertness (dopamine), and social recognition (oxytocin). Peroxynitrites inhibit the transport and metabolism of glucose likely resulting in delusions, wandering, and apathy. Indeed, peroxynitrites cause almost all the phenomena of Alzheimer's disease.

Peroxynitrite scavengers treat Alzheimer's disease. The best peroxynitrite scavengers are compounds containing methoxy and hydroxy groups such as methoxyphenols or hydroxy methoxyflavones. The methoxy group is a good electron donor and increases the abstraction of the hydrogen atom from the hydroxy group, thus scavenging peroxynitrite: ONOO- + 2H+ + 2e-= H20 + N02-. Water in turn helps denitrate amyloid plaques, hyperphosphorylated tau proteins, and the NMDA receptor: Tyrosine-NO2 + H20= Tyrosine-H + H+ + NO3-. Finally, peroxynitrite scavengers partially restore function to g-protein coupled receptors by restoring hydrogen to them.

Amyloid oligomers contribute to this process as follows. The iron in the oligomers converts the nitrite anion into nitrite which can either directly nitrate tyrosine or it can combine with hydrogen peroxide to form more peroxynitrites. As amyloid aggregates it entombs not only iron but also zinc and copper--two heavy metals that are needed for superoxide dismutase to convert superoxide anions into hydrogen peroxide. This lessens the hydrogen peroxide mediated production of peroxynitrites. On the other hand, all the superoxide anions can now react with inducible nitric oxide to produce peroxynitrites.

Without heavy metals, amyloid oligomers and plaques do no damage. However, even with heavy metals both only damage rather than kill neurons. And while metal chelation may lower peroxynitrite levels, it does not in itself stop the peroxynitrite-mediated killing of cells. Many peroxynitrite scavengers though are also metal chelators and thus serve a very useful dual function.

The main source of peroxynitrite formation early in Alzheimer's disease is phospholipase C activation--protein kinase C activation--p38 MAPK activation. As the disease continues phospholipase C activity and in most cases protein kinase C activity decline (when protein kinase C is activated independently from phospholipase C by such things as aluminum fluoride and sodium fluoride--hallucinations become a problem).

As the disease continues, a cycle develops--p38 MAPK causes the formation of peroxynitrites and peroxynitrites via nitration of NMDA receptors, calcium influx, and AMPK activation (which was recently found to be high in Alzheimer's disease)causes the activation of p38 MAPK. The disease can be treated with compounds that either inhibit p38 MAPK or scavenge peroxynitrites or both.

Following is a list of peroxynitrite scavengers containing methoxy and hydroxy groups that have partially reversed Alzheimer's disease in human clinical trials: rosemary essential oil (eugenol) and lemon essential oil (geraniol) via aromatherapy (Jimbo, et al.--lavender and orange were used in the evenings for relaxation), heat-processed ginseng (ferulic acid, vanillic acid, and syringic acid) (Heo, et al.), lemon balm essential oil extract (eugenol, ferulic acid) (Akhondzadeh et al.), citrus peel (hesperidin) (Seki, et al.), and mulberry leaves (ferulic acid, vanillic, syringic, and sinapic acid) (Scrihaikul).

Perhaps there is a chemist out there who can add or rearrange the methoxy and hdyroxy groups to produce even better results. If he or she can, good fortune to them and to all those with Alzheimer's disease or taking care of someone with Alzheimer's disease.

Permalink to Comment

5. Matt on May 30, 2013 5:26 PM writes...

One other comment: the four-ish (one of the "studies" was apparently a joint comment by a lot of separate researchers) separate studies are in some ways disappointing for all the things they didn't do, or did do questionably. They dissolved the microcrystals in organic solvent, or used the free acid form of the compound. Only two actually studied the mouse behavior (those two both found recovery to wild-type memory levels, as I understand). Most did not do pharmacokinetic studies, to understand whether their formulation changes affected availability.

I guess it's the same as the blog-syn results: the variety of approaches is important in robustly reproducing results, but extreme caution must be exercised before suggesting they invalidate the earlier result. Tests to make sure the validaters haven't screwed things up by their various substitutions, or measured an entirely different quantity, etc. Tedious searches to identify pedantic little details of differences, which turn out to be significant. But it seems to me that's science (and any craft, as well-- see vtgmnhRQir4 on youtube).

Permalink to Comment

6. sepisp on May 31, 2013 8:45 AM writes...

#4: I don't think it's the methoxyl group that makes those compounds you list good radical traps. Geraniol has none, for instance. What they do have in common is an unsaturated system susceptible to radical attack. There's a mechanism for you why bexarotene could work.

Permalink to Comment

7. Lane Simonian on May 31, 2013 12:29 PM writes...

For lemon essential oil, it may be the combination of geraniol with other compounds containing methoxy groups that explain its limited peroxynitrite scavenging abilities.

More importantly, the methoxy group does appear to critically enhance the antioxidant capacity of phenolic compounds. To cite one study: "hydrogen atom abstraction is surprisingly easy from intramolecularly hydrogen bonded methoxyphenols, in contrast to intramolecularly hydrogen bonded moleucles." This is why methoxyphenols are the key to scavening and reversing part of the damage done by peroxynitrites and why they are therefore the key to treating Alzheimer's disease.

In regards to bexarotene, there are suggestions that it and other retonic acid receptor agonists inhibit hydrogen peroxide production, so it may be of some limited value, but there are safer and more effective alternatives.

Permalink to Comment

8. Cesare ragazzi on June 14, 2013 9:22 AM writes...

The effect on plaques, although made the article go into Science, was reported by landreth as temporary. When he first presented this work I have asked him if he thought plaque removal is key to treating Alzheimer's, he clearly said NO!!!!

Permalink to Comment

9. Guy Clark on August 19, 2013 7:31 PM writes...

I just discovered this blog. This subject is very personal as I have corticobasal ganglion degeneration -CBGD - and am trying to find a way to slow down/stop and hopefully reverse the damage. My educational background is in biology with some chemistry. This is the first reference I've seen to peroxynitrates and hyperphosphorylation of tau. I've been somewhat successful in slowing the progression by changing my diet -cut out gluten,sugar,soda,processed foods,etc., adding vegetables,fruit,more fish and pastured/grassfed meats, certain spices, coconut oil, and taking brain building supplements like ginkgo biloba,DHA,
Alpha Lipoic Acid, phosphatidylserine, omega-3, and others. I read a paper published in 1988 where they were researching the formation of tau proteins in the brain. The researchers conclude tau proteins are formed and stable in the presence of calcium and calmodulin. Other papers indicate that that the hyperphosphorylated tau proteins are insoluble. Since everything is soluble in something my doctor and I reasoned that it might be pH related. so my doctor and I reasoned that changing the pH of my blood and brain might flush out these hyperphosphorylated tau proteins. At present I am accomplishing this with bicarbonate of soda. I have noticed some slight improvement in symptoms but not much. Also in this reasoning pattern is the fact that I drank a lot of soda which has phosphoric acid and interferes with calcium in bones so we reasoned that it might also do so in the brain. Based on that 1988 paper I reasoned that there was too little calcium for the tau proteins to form correctly and too much phosphorus which caused them to hyperphosphorylate. In Lane's post above he mentions calcium kills brain cells. I haven't seen this elsewhere. So I'm asking for clarification. In addition, how does one keep peroxynitrates out of the system and purge them once you have them? Also, if anyone has any good ideas how to flush out the hyperphosphorylated tau proteins please post suggestions. Thanks in advance for any helpful information.

Permalink to Comment

10. Sara on August 24, 2013 5:33 PM writes...

Hi,my name is Sara I just want to help you but I'm not a doctor but I'm being always interested in health and nutrition since about 13years ago and still now.Now for the hyperphosphorylated tau proteins,you could prevent further damage with an increase dose of the antioxidants,previously reported to be sufficient to prevent neuropathology from the doctors and technology experimental clinical trials.I suggest that you always consult a doctor,check also natural health remedies,essentials oils, in naturalist pharmacy.I did my own research about Alzheimer's disease the cause of it is a chemical named aluminum and it is in a deodorant armpit, perfume,etc.Just check it out on each item you buy that it doesn't go on your skin then it get absorbed in your skin and it goes into your brain that's what causes Alzheimer's disease check labels for free aluminum. Please do your own research you learn a lot, do it for yourself. It was my pleasure to help you hope it was helpful. P.S. Do more research or ask the doctors for how to flush out the hyperphosphorylated tau proteins . Thanks. TO: GUY CLARK, HOPE you got this comment or Advice, and it didn't got lost before you received it.

Permalink to Comment

11. Sara on August 24, 2013 5:34 PM writes...

Hi,my name is Sara I just want to help you but I'm not a doctor but I'm being always interested in health and nutrition since about 13years ago and still now.Now for the hyperphosphorylated tau proteins,you could prevent further damage with an increase dose of the antioxidants,previously reported to be sufficient to prevent neuropathology from the doctors and technology experimental clinical trials.I suggest that you always consult a doctor,check also natural health remedies,essentials oils, in naturalist pharmacy.I did my own research about Alzheimer's disease the cause of it is a chemical named aluminum and it is in a deodorant armpit, perfume,etc.Just check it out on each item you buy that it doesn't go on your skin then it get absorbed in your skin and it goes into your brain that's what causes Alzheimer's disease check labels for free aluminum. Please do your own research you learn a lot, do it for yourself. It was my pleasure to help you hope it was helpful. P.S. Do more research or ask the doctors for how to flush out the hyperphosphorylated tau proteins . Thanks. TO: GUY CLARK, HOPE you got this comment or Advice, and it didn't got lost before you received it.

Permalink to Comment

12. Barry on September 28, 2013 9:29 PM writes...

@Lane Simonian
Uric acid is a strong peroxynitrite scavenger. Do persons with gout have a lower incidence or slower progression of Alzheimer's Disease (AD)?

If you've seen studies showing "partially reversed" AD, should've posted links. Where's the beef?

Permalink to Comment

13. Bill G. on October 15, 2013 1:04 AM writes...

If I've got this right, plaques are damaged protein fragments that clump together, leaving troublesome deposits that might act like bio-electric insulators, or simply obstruct the flow of blood by collecting on arterial walls.
The thing I find curious is certain apolipoproteins have been indicated by more than one research study as playing a vital role in the dissolving, or forming of these plaques within the body.
Apolipoprotein E-4 (ApoE-4) is indicated as a contributor to amiliod plaques within the brain, and bexarotene for dissolving those plaques. A different series of studies indicated ApoA-1 Milano, a mutated version of the ApoA-1, as being directly responsible for dissolving artery clogging plaques within the human blood stream. ApoA-1 needed to be administered intravenously, because oral preparations failed to reproduce any significant positive results. Bexarotene studies on the other hand used oral solutions simply because that's how it's administered for FDA approved cancer treatments.
When transitioning from animal models to human, the digestive systems might pose a significant delivery breakdown of chemicals introduced orally.
Just a thought...

Permalink to Comment

14. linda on May 21, 2014 7:47 AM writes...

To Lane Simonian- what is your educational background or degrees? I would find it helpful if people placing comments on this site listed their background - it would help me differentiate between comments coming from a strong knowledge base vs. random info gleaned from the internet.

Permalink to Comment

15. Lane Simonian on August 3, 2014 5:20 PM writes...

I have not revisited this entry in a long time, but here are some answers to the questions posed.

Barry: People with gout rarely if ever get multiple sclerosis and multiple sclerosis is another disease in which peroxynitrites play a role. Here is an explanation for why the uric acid--dementia link is not as strong.


In this large, population-based cohort study, serum uric acid levels were not associated with the risk of dementia or with cognitive function later in life. However, after adjustment for several cardiovascular risk factors, higher serum uric acid levels were associated with a decreased risk of dementia and better cognitive function later in life. The age- and sex-adjusted analyses showed no clear association between serum uric acid levels and the risk of dementia, or cognitive function later in life. However, higher levels of uric acid were associated with an increased risk of cardiovascular disease and mortality. After adjustment for several cardiovascular risk factors, a possible protective effect of uric acid was unmasked: higher levels of uric acid were associated with a lower risk of dementia and better cognitive function later in life.

And the studies in which peroxynitrite scavengers have partially reversed Alzheimer's disease:

Psychogeriatrics. 2009 Dec;9(4):173-9. doi: 10.1111/j.1479-8301.2009.00299.x.
Effect of aromatherapy on patients with Alzheimer's disease.
Jimbo D1, Kimura Y, Taniguchi M, Inoue M, Urakami K.
Author information
Abstract
OBJECTIVE:
Recently, the importance of non-pharmacological therapies for dementia has come to the fore. In the present study, we examined the curative effects of aromatherapy in dementia in 28 elderly people, 17 of whom had Alzheimer's disease (AD).

METHODS:
After a control period of 28 days, aromatherapy was performed over the following 28 days, with a wash out period of another 28 days. Aromatherapy consisted of the use of rosemary and lemon essential oils in the morning, and lavender and orange in the evening. To determine the effects of aromatherapy, patients were evaluated using the Japanese version of the Gottfries, Brane, Steen scale (GBSS-J), Functional Assessment Staging of Alzheimer's disease (FAST), a revised version of Hasegawa's Dementia Scale (HDS-R), and the Touch Panel-type Dementia Assessment Scale (TDAS) four times: before the control period, after the control period, after aromatherapy, and after the washout period.

RESULTS:
All patients showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy. In particular, patients with AD showed significant improvement in total TDAS scores. Result of routine laboratory tests showed no significant changes, suggesting that there were no side-effects associated with the use of aromatherapy. Results from Zarit's score showed no significant changes, suggesting that caregivers had no effect on the improved patient scores seen in the other tests.

CONCLUSIONS:
In conclusion, we found aromatherapy an efficacious non-pharmacological therapy for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients.

Eugenol in rosemary essential oil is a methoxyphenol. Geraniol in lemon essential oil supposedly contains a methoxyphenol residue. Lavender and orange which contain linalool were used for relaxation as eugenol can increase stress in some people with dementia.

Abstract:
Eugenol (4-allyl-2-methoxyphenol) is a fragrant compound that is commonly contained in various sorts of plants, especially in spices and medicinal herbs. Eugenol has been used for dental analgesic, which also has anticonvulsive and anti-microbial activities. Besides, anti-inflammatory and antioxidative activities of eugenol are known. A body of evidence suggests that eugenol can be used as a drug for treatment of Alzheimer's disease (AD). According to recent reports, the extract of a medicinal plant Rhizoma Acori Graminei (RAG) alleviates neurotoxicity induced by amyloid beta peptides (Aβ) in vitro and the active constituent of RAG is eugenol. Eugenol inhibits Aβ-induced excessive influx of calcium ion into neurons that causes neuronal death. Moreover, eugenol possesses an antidepressant-like activity. Eugenol, like other antidepressants, increases expression of brain-derived neurotrophic factor (BDNF) gene in the hippocampus, which is necessary for an antidepressant to exhibit its activity. Furthermore, eugenol inhibits monoamine oxidase A (MAO-A) and may restore monoamines that are decreased in the brain of patients with depression. Thus, eugenol can be a good medicine for AD and depression. Here we suggest that eugenol and its analogs can be used also for other diseases of the central nervous system (CNS) including Parkinson's disease (PD). This article reviews the previous investigations concerning effects of eugenol including its analogs on the CNS and describes perspectives of this highly potential compound.

For Guy Clark: it is not calcium per se that is the problem but the influx of calcium which generates more peroxynitrites and kills more neurons.

Lemon balm essential oil contains both eugenol and linalool. The results of a well-conducted study on the use of a lemon balm extract for the treatment of Alzheimer's disease:

Melissa officinalis extract in the treatment of patients with mild to moderate Alzheimer's disease: a double blind, randomised, placebo controlled trial
S Akhondzadeh, M Noroozian, M Mohammadi, S Ohadinia, A Jamshidi, and M Khani
Author information ► Copyright and License information ►
This article has been cited by other articles in PMC.
Abstract
Objective: To assess the efficacy and safety of Melissa officinalis extract using a fixed dose (60 drops/day) in patients with mild to moderate Alzheimer's disease.

Design: A four month, parallel group, placebo controlled trial undertaken in three centres in Tehran, Iran.

Methods: Patients with mild to moderate Alzheimer's disease aged between 65 and 80 years (n = 42; 18 women, 24 men) with a score of ≥ 12 on the cognitive subscale of Alzheimer's disease assessment scale (ADAS-cog) and ≤ 2 on the clinical dementia rating (CDR) were randomised to placebo or fixed dose of Melissa officinalis extract. The main efficacy measures were the change in the ADAS-cog and CDR-SB scores compared with baseline. Side effects were systematically recorded.

Results: At four months, Melissa officinalis extract produced a significantly better outcome on cognitive function than placebo (ADAS-cog: df = 1, F = 6.93, p = 0.01; CDR: df = 1, F = 16.87, p

Conclusions: Melissa officinalis extract is of value in the management of mild to moderate Alzheimer's disease and has a positive effect on agitation in such patients.

Panax ginseng contains a variety of methoxyphenols including ferulic acid and syringic acid.

J Med Food. 2009 Feb;12(1):124-30. doi: 10.1089/jmf.2007.0646.
Evaluation of the peroxynitrite scavenging activity of heat-processed ginseng.
Kang KS1, Tanaka T, Cho EJ, Yokozawa T.
Author information
Abstract
To ascertain the principal active peroxynitrite (ONOO(-)) scavenging components of heat-processed Panax ginseng C.A. Meyer (sun ginseng [SG]), the ONOO(-) scavenging activities of fractions and components of SG were compared. The results demonstrated that the ONOO(-) scavenging ability of SG was due to its ether fraction containing phenolic compounds. High-performance liquid chromatography analysis and ONOO(-) scavenging activity tests of the phenolic acids contained in SG identified vanillic acid, ferulic acid, p-coumaric acid, syringic acid, and maltol as the main active ONOO(-) scavenging components of SG. The ONOO(-) scavenging activities of phenolic acids and maltol were dependent on the degrees of their proton donating ability.

Improvement of Cognitive Deficit in Alzheimer’s Disease Patients by Long Term Treatment with Korean Red Ginseng
Jae-Hyeok Heo,1 Soon-Tae Lee,2,3 Min Jung Oh,2,3 Hyun-Jung Park,2,3 Ji-Young Shim,2,3 Kon Chu,2,3 and Manho Kim2,3,*
Author information ► Article notes ► Copyright and License information ►
This article has been cited by other articles in PMC.
Go to:
Abstract
A 24-week randomized open-label study with Korean red ginseng (KRG) showed cognitive benefits in patients with Alzheimer’s disease. To further determine long-term effect of KRG, the subjects were recruited to be followed up to 2 yr. Cognitive function was evaluated every 12 wk using the Alzheimer’s Disease Assessment Scale (ADAS) and the Korean version of the Mini Mental Status Examination (K-MMSE) with the maintaining dose of 4.5 g or 9.0 g KRG per d. At 24 wk, there had been a significant improvement in KRG-treated groups. In the long-term evaluation of the efficacy of KRG after 24 wk, the improved MMSE score remained without significant decline at the 48th and 96th wk. ADAS-cog showed similar findings. Maximum improvement was found around week 24. In conclusion, the effect of KRG on cognitive functions was sustained for 2 yr follow-up, indicating feasible efficacies of long-term follow-up for Alzheimer’s disease.

Nutr Neurosci. 2012 Jul 9. [Epub ahead of print]
Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's disease.
Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, Kim M.
Abstract
OBJECTIVES:
Ginseng has been reported to improve cognitive function in animals and in healthy and cognitively impaired individuals. In this study, we investigated the efficacy of a heat-processed form of ginseng that contains more potent ginsenosides than raw ginseng in the treatment of cognitive impairment in patients with moderately severe Alzheimer's disease (AD).

METHODS:
Forty patients with AD were randomized into one of three different dose groups or the control group as follows: 1.5 g/day (n = 10), 3 g/day (n = 10), and 4.5 g/day (n = 10) groups, or control (n = 10). The Alzheimer's Disease Assessment Scale (ADAS) and Mini-Mental State Examination (MMSE) were used to assess cognitive function for 24 weeks.

RESULTS:
The treatment groups showed significant improvement on the MMSE and ADAS. Patients with higher dose group (4.5 g/day) showed improvements in ADAS cognitive, ADAS non-cognitive, and MMSE score as early as at 12 weeks, which sustained for 24-week follow-up.

DISCUSSION:
These results demonstrate the potential efficacy of a heat-processed form of ginseng on cognitive function and behavioral symptoms in patients with moderately severe AD.

All of these were small studies, but in each case peroxynitrite scavengers partially reversed Alzheimer's disease leading to improvement in cognition, in behavior, or both.

Guy Clark--you are doing the right things and I hope that you continue to improve. Everything you have cut out increases the production of peroxynitrites and everything you are taking scavenge peroxynitrites, reverses part of their damage, and prevent their buildup.

The problem with hyperphosphorylation of tau proteins may not be due to excessive phosphorylation but with nitration.


FASEB J. 2006 Jul;20(9):1431-42.
Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms.
Zhang YJ1, Xu YF, Liu YH, Yin J, Li HL, Wang Q, Wang JZ.
Author information
Abstract
To investigate the upstream effector that led to tau hyperphosphorylation, nitration, and accumulation as seen in Alzheimer's disease brain, and the underlying mechanisms, we bilaterally injected SIN-1, a recognized peroxynitrite donor, into the hippocampus of rat brain. We observed that the level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h after drug administration, and these alterations were prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. Concomitantly, we detected a significant activation in glycogen synthase kinase-3beta (GSK-3beta) and p38 MAPKs, including p38alpha, p38beta, and p38delta, but no obvious change was measured in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, in which the activity of 20S proteasome was significantly arrested in SIN-1-injected rats. Further studies demonstrated that the hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis. These results provide the first in vivo evidence showing that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation. Our findings reveal a common upstream stimulator and a potential therapeutic target for Alzheimer-like neurodegeneration.

To highlight the most important sentence:
Further studies demonstrated that the hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis.

The way to denitrate tau and other compounds containing tyrosine is with water.

Mol Cell Biochem. 1999 Nov;201(1-2):11-6.
Denitration of peroxynitrite-treated proteins by 'protein nitratases' from rat brain and heart.
Kuo WN1, Kanadia RN, Shanbhag VP, Toro R.
Author information
Abstract
Putative 'protein nitratases,' which catalyze denitration of peroxynitrite (PN)-treated proteins, were detected in the homogenate/crude extract of rat brains and hearts. Nitratase activity was monitored by the decreased intensity of nitrotyrosine immunoreactive-bands in Western blot and increased nitrate level in dialysate of incubation mixture, which contained homogenate/crude extract, protease inhibitors and a PN-treated substrate, such as treated histone (III-S), BSA or invertase. Enhanced activity of nitratases was noted by preincubating crude extract with Ca2+. In addition, at least two types of nitratases may occur: type I, reductant-dependent, and type II, reductant- independent. Furthermore, upon denitration, the activity of PN-treated invertase increased to the same activity level of the untreated invertase. The overall reaction catalyzed by nitratases for denitration of nitrotyrosine residues in protein could be as follows: Protein-Tyr-NO2 + H2O --> Protein-Tyr-H + H+ + NO3-. The nitration/denitration of protein-tyrosine may be crucial in regulating signal transduction.

And as it would be peroxynitrite scavengers produce water: ONOO- + 2e- + 2H+= H20 + NO2-.

The methoxy group donates the electrons and increases the hydrogen donating capacity of the phenol group. This is why methoxyphenols are such good peroxynitrite scavengers and why they have partially reversed Alzheimer's disease in clinical trials.

Sara: aluminum in various forms can contribute to Alzheimer's disease. Aluminum fluoride poses a particular risk.

Linda: I have an M.A. in political science and a Ph.D. in history (environmental history), but I also have some background in biology. I have very little background in chemistry (other than biochemistry) but the two reactions listed above (denitration of tau proteins and the scavenging of peroxyntrites) are the only two one really needs to understand in regards to the treatment Alzheimer's disease.

I have studied Alzheimer's disease for ten years: it is not cutting and pasting or gleaning information from the internet. It is anaylzing a great deal of information and putting it together in a coherent story to support a hypothesis that is nearly twenty years old and backed by some of the best Alzheimer's researchers in the world.


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