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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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December 11, 2013

David Cameron, The Press, Alzheimer's, and Hope

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Posted by Derek

One should be cheering the news that Great Britain will double funding for Alzheimer's and dementia research. But there's something odd about the way it's being presented, at least to my eyes. Here's a story from the Guardian that might illustrate what I mean:

The health secretary, Jeremy Hunt, said he hoped the dementia summit would have the same effect as the G8 summit in Gleneagles on HIV/Aids in 2005.

"Today should be an optimistic day," he told BBC Breakfast. "Tony Blair had the G8 summit in Gleneagles in 2005 on HIV/Aids and actually that did turn out in retrospect to be a turning point in the battle against Aids.

"I think if you bring the world's leaders together, health ministers from across the world, and we are all resolved that we really are going to do something about this as we face up to an ageing society."

If 2005 was some sort of widely-recognized turning point in HIV control, I must have missed it. I'll be glad to be corrected, but the last sentence in that quote makes me wonder, because it isn't a sentence. Try it out: the first part isn't connected with the second. He thinks that if you bring the world's leaders together, then. . .what will happen? "If" implies some sort of resolution in a sentence, and there isn't any. How about the second part? They're all resolved that they're really going to do something - fine, but isn't that the easiest part? The simplest part? I mean, coming out and saying that you'd like to "do something" about a problem that everyone would like to see solved is not that big a step, is it?

Well, doubling research funding is certainly doing something, there's no taking away from that. Much is made in the various press articles about Lilly's Alzheimer's scan, which Britain's National Heath Service is going to make available to some patients. Now, Lilly has been talking bravely about Alzheimer's for some time now, and to be fair to them, they've been spending pretty bravely, too. No doubt their hope has been that their imaging agent would match up with some successful therapy they'd develop, but the "successful therapy" part has been the hard one.

But British Prime Minister David Cameron has also been talking about finding a cure by 2025. I hope we do - I may need it by then - but it's going to take a generous slug of luck for that to happen. I don't hold out much hope for anything currently in development as a cure, although I'd like to be wrong about that. And something that's not in development would barely make it through, on an optimistic timetable, by 2025. We certainly don't know enough about Alzheimer's to say that we're on track, so someone will have to get lucky. You wouldn't know that from the British newspapers, though. They've also been excited about the potential of Eli Lilly's solanezumab, which must make the UK the only area outside of Indianapolis where that state of mind obtains.

That's the part that worries me about the public statements in this area. Politicians (and CEOs) are prone to ringing declarations that make it sound as if all that's really needed is gumption and willpower - good faith will carry the day. But that just isn't true in research. It really isn't. Nerve and perseverance are necessary, and how, but they're nowhere near sufficient. To pretend otherwise is to engage in magical thinking, and the history of Big Proclamations in the biomedical field should be enough to prove that to anyone.

Back in 2003, we were supposedly going to eliminate death and suffering from cancer by 2015 (and Senator Arlen Spector asked if maybe we couldn't move the timetable up to 2010). On a lesser level, back in 2009, there were statements that a cure for the common cold was at hand. Sorry about that. The British press has a particular weakness for proclaimed Alzheimer's cures, not that the US press doesn't go for them, too.

No, saying it will not make it so. I don't know how to make it so, other than by spending a lot of money and a lot of time, and working really hard, and hoping for the best. But that's not the stuff of headlines.

Comments (60) + TrackBacks (0) | Category: Alzheimer's Disease | Cancer


COMMENTS

1. Anonymous on December 11, 2013 12:50 PM writes...

"The British press has a particular weakness for proclaimed Alzheimer's cures".

Especially the BBC - every time someone publishes a paper testing a molecule on some cells, the BBC has heralded a major breakthrough in AD and a cure on the horizon. Even if the cells have nothing to do with AD!

Permalink to Comment

2. bank on December 11, 2013 1:22 PM writes...

I would say that there is some additional benefit to Big Proclamations such as Cameron's one on Alzheimer's disease, and that is how it affects the attitude of the public.

Alzheimer's disease is sometimes regarded as a natural consequence of ageing, and therefore inevitable. This leads to a defeatist attitude among the public and even those who care for people with dementia, with a knock-on effect of reducing support from government and donations to non-profits.

"A cure by [whenever]" is a rhetorical device and shouldn't be taken any more seriously, in a scientific sense, than Richard Nixon's War on Cancer in 1971.

Permalink to Comment

3. MoMo on December 11, 2013 1:25 PM writes...

Sure, it sounds good and is the kind of sensationalism that gets the British all worked up, but at that rate of investment, over 11 years it represents a measly 7% increase per year. Subtract 3% for inflation and it is back to square one with a 4% increase in funding, yearly.

It would be better to spend the extra money on more potent antioxidants and teas research.

Permalink to Comment

4. Anonymous on December 11, 2013 1:36 PM writes...

"Cameron said he would double funding research from £66m in 2015 to £122m in 2025"

Given that AD costs the US alone $100 Billion per year (and I assume at least £10 Billion per year to the UK), and these costs are expected to DOUBLE by 2025, £122 million is really quite pathetic! Talk about cracking a nut with a sledge hammer, this is like trying to crack a coconut with a toffee hammer.

Permalink to Comment

5. DrugA on December 11, 2013 1:40 PM writes...

Other than a few specific types of cancer, has any non-infectious disease ever been cured by drugs? I can't think of any.

That doesn't mean that pharmacotherapy hasn't been highly successful for a lot of conditions, but suggests that talk of "cures" may be a bit optimistic.

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6. Lane Simonian on December 11, 2013 1:50 PM writes...

I am going to try to state this as calmly as possible: there will be no cure for Alzheimer's disease until the right target is found. Amyloid is not the right target. Approximately a third of autopsies find significant buildup of amyloid in people without Alzheimer's disease. And even by Eli Lilly's admission about 20 percent of the people they thought had Alzheimer's disease in their studies did not have amyloid.

Everyone with Alzheimer's disease will have one of the following: the amyloid precursor protein, amyloid oligomers, or amyloid plaques. All you need for Alzheimer's disease is the precursor protein because the same pathways (the activation of tyrosine kinase receptors and protein kinase C alpha)that lead to the precursor protein also lead to the cause of Alzheimer's disease (peroxynitrites).

J Neurochem. 2001 Jul;78(1):109-20.
C-terminal fragment of amyloid precursor protein induces astrocytosis.
Bach JH, Chae HS, Rah JC, Lee MW, Park CH, Choi SH, Choi JK, Lee SH, Kim YS, Kim KY, Lee WB, Suh YH, Kim SS.
Source
Department of Anatomy, College of Medicine, BioGrand Inc., and MRC, Chung-Ang University, 221 Huksuk-dong, Dongjak-ku, Seoul 156-756, Korea.

Abstract
One of the pathophysiological features of Alzheimer's disease is astrocytosis around senile plaques. Reactive astrocytes may produce proinflammatory mediators, nitric oxide, and subsequent reactive oxygen intermediates such as peroxynitrites. In the present study, we investigated the possible role of the C-terminal fragment of amyloid precursor protein (CT-APP), which is another constituent of amyloid senile plaque and an abnormal product of APP metabolism, as an inducer of astrocytosis. We report that 100 nM recombinant C-terminal 105 amino acid fragment (CT105) of APP induced astrocytosis morphologically and immunologically. CT105 exposure resulted in activation of mitogen-activated protein kinase (MAPK) pathways as well as transcription factor NF-kappaB. Pretreatment with PD098059 and/or SB203580 decreased nitric oxide (NO) production and nuclear factor-kappa B (NF-kappaB) activation. But inhibitors of NF-kappaB activation did not affect MAPKs activation whereas they abolished NO production and attenuated astrocytosis. Furthermore, conditioned media derived from CT105-treated astrocytes enhanced neurotoxicity and pretreatment with NO and peroxynitrite scavengers attenuated its toxicity. These suggest that CT-APP may participate in Alzheimer's pathogenesis through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction.

Amyloid oligomers and plaques additionally require the release of intracellular calcium and this does not always happen (caffeine and heparin, for instance, inhibit the release of intracellular calcium). On the other hand, with a good antioxidant system one may have plaques without Alzheimer's disease.

The peroxynitrite hypothesis for Alzheimer's disease was offered 15 years ago by the late Mark A. Smith, who liked to remark that lots of people liked to poke a stick in his eye but none were ever able to prove him wrong.

And just one last anonymous quote on this subject:

[Clinical trials with over-the-counter supplements have concentrated either on items which suppress inflammation, or on antioxidants which scavenge oxygen derived free radicals. Most of these items have proved to be worthless in the treatment of Alzheimer's disease. Similarly most drugs used to treat Alzheimer's disease do little to slow the deterioration, but instead offer a mild temporary
symptom relief. However, evidence has been accumulating that the primary driver of Alzheimer's disease is a nitrogen derived free radical called peroxynitrite, which may mediate both amyloid and tau accumulation as well as their toxicity. Excellent results have been obtained with peroxynitrite scavengers, with reversals of Alzheimer's disease in human clinical trials being repeatedly demonstrated. IMHO, the only thing which may be preventing the abolition of
Alzheimer's disease is the mental inertia of scientists, as well as the bureaucrats who fund them. Unfortunately, most bureaucrats keep throwing money into repeatedly testing discredited interventions, while ignoring successful ones. Common sense is anything but...]

Permalink to Comment

7. Chris on December 11, 2013 1:51 PM writes...

It is good that Cameron has shone the spotlight on the issues of AD, and as others have said the amount of money is not sufficient to realistically find a cure. I can't help but feel that some of the charities in the UK should look at Cancer Research UK who have built a pretty impressive machine to fund Cancer research.
I'm not convinced that governments focus on things that will become a problem for the next generation.

Permalink to Comment

8. luigi on December 11, 2013 2:11 PM writes...

@4 - being pathetic must be contagious - Cameron's comments are no less pathetic and misplaced than those of Obama's 2012 funding of AD at the NIH for a cure - again by 2025. Being vague, delusional and dismissing the really hard part is a characteristic of politicians. Many may also remember Monty Python's Blue Peter sketch where John Cleese's advice on getting really rich was to "think of something interesting"

Permalink to Comment

9. Jed on December 11, 2013 2:57 PM writes...

"I don't hold out much hope for anything currently in development as a cure, although I'd like to be wrong about that."

What do you think about the Merck (Schering) BACE inhibitor MK-8931 in PhII/III? The APP mutation that prevents BACE cleavage and protects against AD seems like excellent target validation. The question seems to be whether a drug can get to the target and whether it will be safe. Another issue is clinical trial design and choosing the right patient population. I really hope this one works!

This is coming from someone who spent over 4 years working unsuccessfully on gamma secretase modulators. I still believe the amyloid pathway is critical, the problem is finding the right drug.

Permalink to Comment

10. Anonymous on December 11, 2013 2:58 PM writes...

That will be this Jeremy Hunt then ...

Early Day Motion signed in 2007:

That this House welcomes the positive contribution made to the health of the nation by the NHS homeopathic hospitals; notes that some six million people use complementary treatments each year; believes that complementary medicine has the potential to offer clinically-effective and cost-effective solutions to common health problems faced by NHS patients, including chronic difficult to treat conditions such as musculoskeletal and other chronic pain, eczema, depression, anxiety and insomnia, allergy, chronic fatigue and irritable bowel syndrome; expresses concern that NHS cuts are threatening the future of these hospitals; and calls on the Government actively to support these valuable national assets.

Permalink to Comment

11. Anonymous on December 11, 2013 3:00 PM writes...

David Cameron is a chicken hawk.

Permalink to Comment

12. Lane Simonian on December 11, 2013 3:25 PM writes...

Jed, early on the beta secretase is a good target. This secretase is controlled by tyrosine receptor kinases and protein kinase C alpha.

Platelet-derived growth factor induces the beta-gamma-secretase-mediated cleavage of Alzheimer's amyloid precursor protein through a Src-Rac-dependent pathway.

Mol Cell Biol. 2004 Sep;24(17):7578-97.
Protein kinase Calpha activates c-Src and induces podosome formation via AFAP-110.

The key to preventing Alzheimer's disease is to inhibit tyrosine kinase receptors and protein kinase C. Once the disease has progressed, in most cases, tyrosine kinase receptors and protein kinase C are already inhibited due to nitration and oxidation and then the main problem becomes the activation of NMDA receptors.

Permalink to Comment

13. Morten G on December 11, 2013 4:34 PM writes...

So Lilly has a diagnostic? That's pretty encouraging. What's the patent limit on diagnostics?

Permalink to Comment

14. DrSnowboard on December 11, 2013 4:48 PM writes...

If one were cynical, one could argue that Cameron is attempting to offset the removal of benefits and increased taxation that his fiscal policies are / are about to inflict on the aging baby boomer generation. Make a grand gesture towards a great fear of a rapidly ageing segment of the electorate, they may forgive you pilfering the benefits they paid in for.

Permalink to Comment

15. AndrewD on December 11, 2013 4:49 PM writes...

If I was being cynical, which I am, I would observe that in June 2015, there is a general election in the UK. The older generations tend to suffer from dementia and vote in Elections, I suspect vote getting

Permalink to Comment

16. milkshaken on December 11, 2013 6:00 PM writes...

faith-based medicine and drug development by a summit of government officials will revolutionize Alzheimer research. Just imagine the time and cost savings if the governments could waive the required proof of long term safety and efficacy...

Permalink to Comment

17. Lest we forget on December 11, 2013 6:06 PM writes...

Anno domini.

Permalink to Comment

18. Anonymous on December 11, 2013 6:25 PM writes...

16# I assume by 'faith-based' medicine you mean solanezumab! It is worth noting the Brit quoted in the Telegraph article used to work for Lilly. Therefore the exictement is principally in Indianapolis and a small village in the UK called Windlesham were the Lilly Research Centre is located.

Permalink to Comment

19. Nick K on December 11, 2013 6:48 PM writes...

#10: Agreed. This is a terrible indictment of the scientific illiteracy of British politicians. And these people are running the country!

Permalink to Comment

20. BTDT on December 11, 2013 8:05 PM writes...

Not to be picky, but the "war on cancer" goes much farther back than 2003. Just search for: The National Cancer Act of 1971

Permalink to Comment

21. whirlygig on December 11, 2013 10:54 PM writes...

Dat last sentence... @@@@@@

Permalink to Comment

22. Anonymous BMS Researcher on December 12, 2013 12:03 AM writes...

Seems to me we need fundamental new ideas for AD. Old sayings come to mind:

"Nine women cannot produce a baby in one month"

"You can't win the high jump with eight guys who can each jump one foot, you need one guy who can jump eight feet."

Permalink to Comment

23. Dr Jimbo on December 12, 2013 12:28 AM writes...

@#11
I saw a chicken hawk on the bayou today (doing some touristing after ASH), and it's a magnificent bird that I'm sure would take exception to your comparison to that worm Cameron.

Permalink to Comment

24. Hotdog Jack on December 12, 2013 3:14 AM writes...

Cameron is scum, but there _is_ some room for government to help. This era's pharmaceutical giants are extremely slow, conservative, and risk-averse -- and the regulatory agencies that oversee them are much, much worse. With the proper development incentives, and with regulatory 'fast tracking' and leniency taken to an absolute extreme, it's possible that some headway can be made before 2025. The disease would instantly become a much more attractive target to companies of all sizes, and the market can then sort out which treatment is most effective, as has happened many times in the past.

Alzheimer's is just about as bad as it gets. I'd argue that almost no side effect is too severe. The current drug-approval model fails miserably for diseases such as this.

Permalink to Comment

25. petros on December 12, 2013 3:17 AM writes...

And the Health Secretary, over whom one BBC interviewer had a slip of the tongue to start his name with a C, is one of the less inspiring Cabinet Ministers in the UK Government

Permalink to Comment

26. james on December 12, 2013 3:32 AM writes...

@25
It was not one BBC presenter but two in a row in the space of a few hours, I remember that morning well!

Permalink to Comment

27. Leedschemist on December 12, 2013 4:22 AM writes...

yeah J Hunt is almost the definition of a useless cabinet minister; he also believes in homeopathy just what you want from your Health Secretary! The idea is laudable though and any increase in funding for UK science has to be welcomed in the current climate.

Permalink to Comment

28. Anonymous on December 12, 2013 6:37 AM writes...

@6, 12 (Lane Simonian): "The key to preventing Alzheimer's disease is to inhibit tyrosine kinase receptors and protein kinase C. Once the disease has progressed, in most cases, tyrosine kinase receptors and protein kinase C are already inhibited due to nitration and oxidation and then the main problem becomes the activation of NMDA receptors." blah blah blah

You should read a few articles about how hubris (people such as yourself thinking they know more than they really do) is killing drug development in the pharma industry.

Here is one that you should take lessons from, ideally before posting more crap as if you are an absolute authority on the field, while everyone else is stupid:

http://www.tcpinnovations.com/drugbaron/why-hubris-kills-returns-on-pharma-rd/

Permalink to Comment

29. Project Osprey on December 12, 2013 7:47 AM writes...

@5

Cures? Not many no. But perhaps that's a unfair area to pick on. Non-communicable diseases are normally the result of some sort of permament damage to the body, which makes them tricky to treat. It's like trying to cure someone from having lost a arm.
There are a lot of sucessful treatments though. Think of asthma, diabetes, certain autoimune disorders: A generation ago these were dibilitating, even lethal. Now you can live a long life with them. It's not perfect but things are improving.

Permalink to Comment

30. MTK on December 12, 2013 8:02 AM writes...

@29,

Agree. Modern medicine, and the drugs used, has taken many conditions which were once fatal or debilitating and turned them into manageable chronic conditions with acceptable minimal impact on life expectancy and quality. That's a real win and should not be discounted.

@2,

Actually in the late 60's and early 70's a "cure" for cancer was actually thought within reach by many scientists. Certainly not all, but quite a few. Nixon's War on Cancer was more than just a rhetorical device. America had just gone to the moon, for pete's sake. We sort of thought we could accomplish anything if we put our mind to it.

Permalink to Comment

31. johnnyboy on December 12, 2013 10:02 AM writes...

I've been looking into moving to the UK at some point in the future (for personal, rather than work reasons), but frankly, at the salaries that are on offer for life sciences researchers, it's a wonder there's any research still going on there at all. Cameron's 66 million is a case in point: they seem to expect such crumbs to actually make a difference, when it won't even make a dent.

Permalink to Comment

32. NC on December 12, 2013 12:31 PM writes...

They don't expect these crumbs to make a difference - they expect the public to read about it and think "oh! How marvellous the Tories are for science and the economy". The public are not typically scientists!

Permalink to Comment

33. Lane Simonian on December 12, 2013 2:23 PM writes...

#28 It has nothing to do with hubris or blah, blah, blah. It is about trying to move away from pious announcements, miracles of the month, and repeated failures based on an entrenched but largely incorrect hypothesis of the disease. BACE inhibitors if they do not produce major side effects offer some hope, not because they stop the production of amyloid plaques but because if you start far enough upstream they slow down the production of peroxynitrites. Gamma secretases do not work because they slow down the production of amyloid but not of peroxynitrites.

The critical point is that one can have Alzheimer's disease without amyloid plaques. In some people with Alzheimer's disease removing amyloid plaques may help somewthat, but in people who have Alzheimer's disease without the plaques it is not going to help at all.

Alzheimer’s Disease Without Amyloid Plaque

Amyloid plaques have long been thought to be the cause of neuron loss in Alzheimer’s disease. Now researchers report that excess of mutated amyloid precursor protein (APP) inside the neurons is sufficient to induce neuron death.

It is not hubris to point out that certain peroxynitrite scavengers have partially reversed Alzheimer's disease in human clinical trials--they just did. The hubris comes in ignoring these studies because you expect/want a different result.

Permalink to Comment

34. Anonymous on December 12, 2013 2:50 PM writes...

@33, Lane: Did it ever occur to you that a completely different form of amyloid might be the main culprit? There are now hundreds, if not thousands of research papers showing that soluble oligomeric forms of amyloid, not the insoluble plaques are inherently toxic and kill cells, apparently by forming holes in cell membranes, and (in many cases) without the formation of peroxynitrites. You are about 15 years and several hundred papers behind in your thinking.

Permalink to Comment

35. Morten G on December 12, 2013 3:14 PM writes...

@23 a chicken hawk is a (middle aged) gay man who preys on guys around 18-21 yo. I haven't heard this before so I'm not sure if it's being used as a nonce which can both be literal and just an insult.

Permalink to Comment

36. a. nonymaus on December 12, 2013 3:34 PM writes...

Re: 35
I think that in this context, the term Chickenhawk refers to the political creature that engages in warmongering but is not in any danger of being sent abroad.

Permalink to Comment

37. Lane Simonian on December 12, 2013 3:42 PM writes...

#34 Yes, amyloid comes in different forms and yes various forms of amyloid can do damage to the brain, but the failure of amyloid antibodies cannot simply be explained by going after the wrong form of amyloid or starting too late. Damage to neurons can occur well before the formation of either amyloid oligomers or plaques.

If you look at the general and specific damage done in the brain of people with Alzheimer's disease: nitration, oxidation, lipid peroxidation, inflammation, DNA damage, inhibition of neurotransmitter release and synthesis, mitochondrial failure, misfolded proteins, vascular dysfunction, disruption of transport systems, inhibition of the regeneration of neurons, and death of neurons it is all directly or indirectly connected to peroxynitrites. That is why peroxynitrite scavengers likely provide the critical therapeutic strategy for the treatment of Alzheimer's disease.

Permalink to Comment

38. Torson on December 13, 2013 12:40 AM writes...

For all guys above that already have figured out how to cure Alzheimer. The quote is from April 2013.

"Sanofi (SAN), won’t push hard to find an Alzheimer’s treatment because the science isn’t advanced enough to justify the costs to develop a drug, Chief Executive Officer Chris Viehbacher said."

Permalink to Comment

39. Torson on December 13, 2013 12:41 AM writes...

For all guys above that already have figured out how to cure Alzheimer. The quote is from April 2013.

"Sanofi (SAN), won't push hard to find an Alzheimer's treatment because the science isn't advanced enough to justify the costs to develop a drug, Chief Executive Officer Chris Viehbacher said."

Permalink to Comment

40. Anonymous on December 13, 2013 8:36 AM writes...

@37: Complete rubbish. Amyloid antibodies don't work simply because they can't get into the brain and within the brain cells. Their failure to work has nothing to do with amyloid.

And you're wrong about amyloid not forming early enough, because again you are thinking about the visible insoluble plaques which only form later, rather than invisible soluble oligomers. Read some papers, or even better, go out and cure the disease if you already know everything. Either way, shut up until you have a clue.

Permalink to Comment

41. Anonymous on December 13, 2013 9:10 AM writes...

How hard can it be to find political leaders able to string a logical sentence together? At least Jeremy Hunt isn't the secretary for education, I suppose.

Permalink to Comment

42. Lane Simonian on December 13, 2013 10:04 AM writes...

#40 Whether this is true or not, by some means they are reducing amyloid levels to some degree. More importantly let me repeat two findings above regarding the amyloid precursor protein.

Alzheimer’s Disease Without Amyloid Plaque

Amyloid plaques have long been thought to be the cause of neuron loss in Alzheimer’s disease. Now researchers report that excess of mutated amyloid precursor protein (APP) inside the neurons is sufficient to induce neuron death.

Furthermore, conditioned media derived from CT105-treated astrocytes enhanced neurotoxicity and pretreatment with NO and peroxynitrite scavengers attenuated its toxicity. These suggest that CT-APP may participate in Alzheimer's pathogenesis through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction.

And this one on rosmarinic acid (there are a couple dozen other peroxynitrite scavengers that have produced the same results).

Behav Brain Res. 2007 Jun 18;180(2):139-45. Epub 2007 Mar 12.
A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35).

Think people, think. If you have the death of neurons simply in the presence of the amyloid precursor protein, amyloid cannot be the sole cause of Alzheimer's disease. It can be a contributor but it cannot be a sole cause. And if peroxynitrite scavengers attenuate the cytotoxicity of both the amyloid precuror protein and amyloid beta, the most effective peroxynitrite scavengers should be able to partially ameliorate the disease (which they have already done in small-scale clinical trials). It is not hard to put together for someone who is willing to do so.


Permalink to Comment

43. Anonymous on December 13, 2013 11:26 AM writes...

"Think people, think. If you have the death of neurons simply in the presence of the amyloid precursor protein, amyloid cannot be the sole cause of Alzheimer's disease."

That makes no sense at all. If neurons are present, then by definition they are not "simply in the presence of the amyloid precursor protein". Neurons themselves are very complex, comprising millions of compounds. How can you be sure they don't contain *any* amyloid, or even secretase.

Think, Lane, think! Because I'm sick of trying to think for you, you're a waste of space.

Permalink to Comment

44. Lane Simonian on December 13, 2013 2:35 PM writes...

I will grant you that--you cannot be absolute certain. My point, however, is that most of the damage attributed to amyloid precursor proteins or amyloid oligomers or amyloid plaques should be assigned to peroxynitrites instead. Just as one example amyloid angiopathy.

TAT-BH4 counteracts Abeta toxicity on capillary endothelium.
Cantara S, Thorpe PE, Ziche M, Donnini S.
Source
Department Molecular Biology, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy. cantara@unisi.it

Abstract
Oxidative stress is one of the factor contributing to blood brain barrier degeneration. This phenomenon is observed during pathological conditions such as Alzheimer's disease or cerebral amyloid angiopathy in which brain haemorrhages are very frequent. Both diseases are characterized by beta amyloid peptide deposition either in neurons or in vessels. Oxidative stress leads to impairment of mitochondrial functions and apoptotic cell death subsequent to caspases activation. In this paper we demonstrate that BH4 domain of Bcl-xl administrated to endothelial cells as the conjugated form with TAT peptide, reverts Abeta-induced apoptotic cell death by activating a survival programme which is Akt/endothelial nitric oxide synthase dependent.


We confirmed that ONOO- uncouples eNOS by oxidation of tetrahydrobiopterin.

And the human clinical trials with peroxynitrite scavengers for Alzheimer's disease and other forms of dementia.

Eugenol in rosemary essential oil via aromatherapy and lemon balm essential oil via tnicture

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.


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 D, Kimura Y, Taniguchi M, Inoue M, Urakami K.
Source
Department of Biological Regulation, School of Health Science, Faculty of Medicine, Tottori University, Yonago, Japan.

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 aromatherpay, 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 aromatherpay, 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.


J Neurol Neurosurg Psychiatry. 2003 July; 74(7): 863–866.
doi: 10.1136/jnnp.74.7.863
PMCID: PMC1738567

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 ►


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.


Ferulic acid, syringic acid, vanillic acid, p-coumaric acid, maltol in heat-process ginseng.


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.

Ferulic acid (in part in Angelica archangelica)

Geriatr Gerontol Int. 2011 Jul;11(3):309-14. doi: 10.1111/j.1447-0594.2010.00687.x. Epub 2011 Jan 28.

Effect of ferulic acid and Angelica archangelica extract on behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.

Kimura T, Hayashida H, Murata M, Takamatsu J.
Source
Division of Clinical Research, National Hospital Organization Kikuchi Hospital, Kumamoto, Japan. tkimura@kikuti.hosp.go.jp

Abstract
AIM:
The behavioral and psychological symptoms of dementia place a heavy burden on caregivers. Antipsychotic drugs, though used to reduce the symptoms, frequently decrease patients' activities of daily living and reduce their quality of life. Recently, it was suggested that ferulic acid is an effective treatment for behavioral and psychological symptoms. We have also reported several patients with dementia with Lewy bodies showing good responses to ferulic acid and Angelica archangelica extract (Feru-guard). The present study investigated the efficacy of Feru-guard in the treatment of behavioral and psychological symptoms in frontotemporal lobar degeneration and dementia with Lewy bodies.

METHODS:
We designed a prospective, open-label trial of daily Feru-guard (3.0 g/day) lasting 4 weeks in 20 patients with frontotemporal lobar degeneration or dementia with Lewy bodies. Behavioral and psychological symptoms of dementia were assessed at baseline and 4 weeks after the start of treatment, using the Neuropsychiatric Inventory. The Neuropsychiatric Inventory scores were analyzed using the Wilcoxon rank sum test.

RESULTS:
Treatment with Feru-guard led to decreased scores on the Neuropsychiatric Inventory in 19 of 20 patients and significantly decreased the score overall. The treatment also led to significantly reduced subscale scores on the Neuropsychiatric Inventory ("delusions", "hallucinations", "agitation/aggression", "anxiety", "apathy/indifference", "irritability/lability" and "aberrant behavior"). There were no adverse effects or significant changes in physical findings or laboratory data.

CONCLUSION:
Feru-guard may be effective and valuable for treating the behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.

Now you can say these studies are rubbish or crap all you wish, but I challenge you to find any Alzheimer's disease or other dementia treatment that has produced the same result not involving a peroxynitrite scavenger.

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45. Anonymous on December 13, 2013 5:25 PM writes...

"Now you can say these studies are rubbish or crap all you wish, but I challenge you to find any Alzheimer's disease or other dementia treatment that has produced the same result not involving a peroxynitrite scavenger."

As I told you before - but you choose not to listen - soluble oligomers of amyloid have been shown to form toxic non-specific pores in pure synthetic phospholipid bilayers without any peroxynitrites, or even any real cells. And what do you think will happen if you make too many holes in cell membranes? The cells will have to work overtime to maintain equilibrium, hence aberrant signaling, hyperphosphorylation, oxidative stress, inflammation, and pretty much every other problem you can imagine - including peroxynitrites.

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46. Anonymous on December 13, 2013 5:36 PM writes...

Oh, and by the way, *hundreds* of papers (not just one or two) show that many different inhibitors of amyloid aggregation and oligomer formation completely reverse the effects of cell toxicity, apoptosis, depletion of long term potentiation and memory loss in rats, mice, and even zebra fish. The only reason why none of these have worked in humans is most likely to be a PK/delivery problem. Join the dots and the evidence is utterly overwhelming.

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47. Anonymous on December 13, 2013 5:44 PM writes...

And finally, all of the genetic mutations in hereditary forms of AD point directly to amyloid as the main and only upstream pathogenic factor, and nothing else. Peroxynitrites are no more than a symptom that correlates with the downstream effects, but the problem is you believe in your own story as a fact, more than the real facts, because you selectively ignore what doesn't fit, and quote everything that does. That isn't science, it's blind faith, no better than religion from the middle ages.

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48. Lane Simonian on December 13, 2013 6:25 PM writes...

The genetic mutations point to the amyloid precursor protein as linked to Alzheimer's disease--not oligomers or plaques. Now maybe the people who did the studies on the amyloid precursor protein missed the plaques and oligomers. Maybe Eli Lilly missed them, too. Maybe the people who did the clinical trials on peroxynitrite scavengers botched their trials, too. Anything I suppose is possible but not very likely.

Numerous studies have linked the toxicity of amyloid (in whatever form) to peroxynitrites. The pathway to peroxynitrite formation (and the amyloid precursor protein) is phospholipase C, protein kinase C, p38 MAPK, NADPH oxidase (superoxide anions), Nuclear Factor kappa B (inducible nitric oxide), peroxynitrites, NMDA receptor activation, p38 MAPK, peroxynitrites.

The pathway to amyloid plaques is phospholipase C and intracellular calcium release--similar but not the same. Therefore it is possible to have Alzheimer's disease without plaques (or oligomers) and plaques (or oligomers) without Alzheimer's disease.

So the study cited above makes absolute sense.

J Neurochem. 2001 Jul;78(1):109-20.
C-terminal fragment of amyloid precursor protein induces astrocytosis.
Bach JH, Chae HS, Rah JC, Lee MW, Park CH, Choi SH, Choi JK, Lee SH, Kim YS, Kim KY, Lee WB, Suh YH, Kim SS.
Source
Department of Anatomy, College of Medicine, BioGrand Inc., and MRC, Chung-Ang University, 221 Huksuk-dong, Dongjak-ku, Seoul 156-756, Korea.

Abstract
One of the pathophysiological features of Alzheimer's disease is astrocytosis around senile plaques. Reactive astrocytes may produce proinflammatory mediators, nitric oxide, and subsequent reactive oxygen intermediates such as peroxynitrites. In the present study, we investigated the possible role of the C-terminal fragment of amyloid precursor protein (CT-APP), which is another constituent of amyloid senile plaque and an abnormal product of APP metabolism, as an inducer of astrocytosis. We report that 100 nM recombinant C-terminal 105 amino acid fragment (CT105) of APP induced astrocytosis morphologically and immunologically. CT105 exposure resulted in activation of mitogen-activated protein kinase (MAPK) pathways as well as transcription factor NF-kappaB. Pretreatment with PD098059 and/or SB203580 decreased nitric oxide (NO) production and nuclear factor-kappa B (NF-kappaB) activation. But inhibitors of NF-kappaB activation did not affect MAPKs activation whereas they abolished NO production and attenuated astrocytosis. Furthermore, conditioned media derived from CT105-treated astrocytes enhanced neurotoxicity and pretreatment with NO and peroxynitrite scavengers attenuated its toxicity. These suggest that CT-APP may participate in Alzheimer's pathogenesis through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction.

You make it sound like a hundred percent of scientists agree that amyloid oligomers are the cause of Alzheimer's disease. That is not the case. Either you are not following the debate or you choose to ignore it.

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49. Anonymous on December 13, 2013 6:42 PM writes...

"The genetic mutations point to the amyloid precursor protein as linked to Alzheimer's disease--not oligomers or plaques".

No, they all point to amyloid specifically, not APP. For example, some AD mutations cause over-expression of beta or gamma secretase, which convert APP into amyloid. That's just not consistent with APP causing AD.

The reason that not everyone agrees is because they can't see the wood for the trees, because like you, they stick by a story and then pick and choose their facts to support it while ignoring the rest, rather than considering every study as a way to nullify a hypothesis. Amyloid *must* be the ultimate cause of at least all these hereditary forms of AD, because every mutation *directly* increases the amount of amyloid and/or its tendency to aggregate. Thus there is no other way for this genetic information to cause AD, except via amyloid.

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50. Lane Simonian on December 13, 2013 8:16 PM writes...

Here is the problem with your argument; just because a mutation causes amyloid does not mean that amyloid is the cause of Alzheimer's disease. For example, each mutation also increases levels of peroxynitrites.

At least you acknowledge that I am not a lone wolf and that those of us who oppose (or are largely opposed) to the amyloid hypothesis are basing the arguments on facts, just that we are not seeing the bigger picture (so that is a little better than blind faith).

I suppose it is not all or nothing: peroxynitrites contribute to the formation of amyloid and amyloid contributes to the formation of peroxynitrites, so peroxynitrite scavengers may be limiting both. Perhaps, it is just because certain peroxynitrite scavengers enter the brain and amyloid antibodies don't that peroxynitrite scavengers have been more effective at treating the disease than amyloid antibodies. In any case to date, peroxynitrite scavengers are the only agents that have partially reversed Alzheimer's disease in human clinical trials.

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51. Anonymous on December 14, 2013 4:55 AM writes...

"Here is the problem with your argument; just because a mutation causes amyloid does not mean that amyloid is the cause of Alzheimer's disease. For example, each mutation also increases levels of peroxynitrites."

And here's your problem: You fail to appreciate that genes code for proteins/peptides, and genetic mutations code for changes in proteins/peptides, not peroxynitrites. The genetic code was cracked in the middle of the last century.

Permalink to Comment

52. Lane Simonian on December 14, 2013 12:23 PM writes...

The mutations by inhibitng a particular pathway (the neuroprotective phosphatidylinositol 3 kinase/Akt pathway) indirectly increase the production of peroxynitrites.

A couple of more studies to try to illustrate the peroxynitrite hypothesis of Alzheimer's disease.

Activation of microglial NADPH oxidase is synergistic with glial iNOS expression in inducing neuronal death: a dual-key mechanism of inflammatory neurodegeneration

Conclusion
These results suggest a dual-key mechanism, whereby glial iNOS or microglial NOX activation alone is relatively benign, but if activated simultaneously are synergistic in killing neurons, through generating peroxynitrite. This mechanism may mediate inflammatory neurodegeneration in response to cytokines, bacteria, ATP, arachidonate and pathological prions, in which case neurons may be protected by iNOS or NOX inhibitors, or scavengers of NO, superoxide or peroxynitrite.

Peroxynitrite Mediates Neurotoxicity of Amyloid β-Peptide1–42- and Lipopolysaccharide-Activated Microglia
Zhong Xie1, Min Wei1, Todd E. Morgan1, Paola Fabrizio1, Derick Han2, Caleb E. Finch1,*, and Valter D. Longo1,*
+Show Affiliations

These results implicate peroxynitrite as a mediator of the toxicity of activated microglia, which may play a major role in Aβ1–42 neurotoxicity and Alzheimer's disease.

If your hypothesis is correct that amyloid oligomers poke holes in cell membranes, then the inflammation would result in more production of peroxynitrites. But in studies where no amyloid was detected, there was still the death of neurons, because you can have the peroxynitrite-mediated death of neurons without amyloid (or with little amyloid). So amyloid is not the entirely wrong target, it is just not entirely the right target.

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53. Anonymous on December 14, 2013 1:36 PM writes...

@52: You're also ignoring the connection between peptide or protein aggregation and so many other neurodegenerative diseases, like Parkinson's (synuclein), ALS (SOD), CJD (prions), Huntington's (polyglutamine), and at least 20 others. All have been shown to form amyloid like pores in cell membranes. What about peroxynitrotes in those cases? Are you saying that they, rather than prions cause CJD? If so they will have to cancel one or two Nobel prizes!

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54. Lane Simonian on December 14, 2013 6:02 PM writes...

It is possible that peroxynitrites change the function and form of prions.

J Neurochem. 2003 Dec;87(6):1456-70.
Selective prion protein binding to synaptic components is modulated by oxidative and nitrosative changes induced by copper(II) and peroxynitrite in cholinergic synaptosomes, unveiling a role for calcineurin B and thioredoxin.
Morot-Gaudry-Talarmain Y, Rezaei H, Guermonprez L, Treguer E, Grosclaude J.
Source
Laboratoire de Neurobiologie Cellulaire et Moléculaire, CNRS, Gif-sur-Yvette, France. morot@nbcm.cnrs-gif.fr

Abstract
Choline acetyltransferase (ChAT) and choline transport are decreased after nitrosative stress. ChAT activity is altered in scrapie-infected neurons, where oxidative stress develops. Cellular prion protein (PrPc) may play a neuroprotective function in participating in the redox control of neuronal environment and regulation of copper metabolism, a role impaired when PrPc is transformed into PrPSc in prion pathologies. The complex cross-talk between PrPc and cholinergic neurons was analyzed in vitro using peroxynitrite and Cu2+ treatments on nerve endings isolated from Torpedo marmorata, a model of the motoneuron pre-synaptic element. Specific interactions between solubilized synaptic components and recombinant ovine prion protein (PrPrec) could be demonstrated by Biacore technology. Peroxynitrite abolished this interaction in a concentration-dependent way and induced significant alterations of neuronal targets. Interaction was restored by prior addition of peroxynitrite trapping agents. Cu2+ (in the form of CuSO4) treatment of synaptosomes triggered a milder oxidative effect leading to a bell-shaped increase of PrPrec binding to synaptosomal components, counteracted by the natural thiol agents, glutathione and thioredoxin. Copper(II)-induced modifications of thiols in several neuronal proteins. A positive correlation was observed between PrPrec binding and immunoreactive changes for calcineurin B and its partners, suggesting a synergy between calcineurin complex and PrP for copper regulation.

For other neurodegenerative disease the seminal work is Pacher, Beckham, Liaudet, Nitric Oxide and Peroxynitrite in Health and Disease.

Again amyloid and peroxynitrites form through similar but not exact pathways. That is why both are often present in many neurodegenerative diseases and while amyloid may very well contribute to the formation of peroxynitrites (and according to many authors this accounts for its neurotoxicity) it is not the sole cause.

If you remove the amyloid, the damage done by peroxynitrites remains, if you scavenge and reverse part of the damage done by peroxynitrites you not only likely lower amyloid levels you also treat the primary cause of the disease (if the hypothesis is correct).

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55. Anonymous on December 14, 2013 7:19 PM writes...

@54 "It is possible that peroxynitrites change the function and form of prions."

Now it's blatantly clear that you are grasping at straws to stick with your story. As I said, that's not science, it's blind faith, and you're about as likely to be open and consider alternative mechanisms in light of all the evidence as the Pope is to convert to Islam. I may as well talk to a wall, and so I'll stop now, thanks.

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56. The Ump on December 17, 2013 11:45 PM writes...

@anonymous and Lane Simonian: let me get this straight before this comment thread gets any longer.

In the blue corner we have the claim that peroxynitrates are the cause of Alzheimers, that compounds that scavenge them can reverse the symptoms, and that a bunch of people have shown this (as illustrated by the citations).

In the red corner we have anon, who pins the blame squarely on amyloid.

Over in the cheap seats we have me, who wonders: if the first theory is correct, why isn't Big Pharma all over this and analyzing witch hazel or whatever it is six ways to sunday in the hopes of producing the perfect blockbuster drug for the baby boomers? Extraordinary claims require extraordinary evidence, after all. But also wondering if the industry could be misled down one path (say, It's All Amyloid's Fault) by a sort of pharmacological groupthink.

OK, flame away.

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57. Anonymous on December 18, 2013 10:31 AM writes...

*lol* 56

Amyloid deposits are observed in the brains of AD patients. Fact.

Presenilin - comprising gamma secretase, the protein that processes amyloid precursor protein down the amyloidogenic pathway, has been shown to be mutated in patients with familial Alzheimer's Disease. Fact.

A mutation in beta secretase, another protein that processes APP, is protective against AD. Fact.

There's plenty of wiggle room around those ideas. i.e. sporadic AD is not the same as familial AS. For example, presenilin and APP don't show up on the GWAS for sporadic AD.

As for Lane's claims, I wrote quite a lengthy message to him about it just over a year ago. He is not scientifically trained, and i think is over-interpreting alot of what essentially amount to social interventions with AD patients. In the early-, and even mid- stages of the disease, very large effects can be seen from relatively small interventions, aromatheraoy being one, but getting the patient a dog, or attending art classes another. I'm not sure how the latter effect peroxynitrite levels.

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58. Lane Simonian on December 18, 2013 10:45 AM writes...

I was going to retire from this particular discussion, but this question is too important to ignore.

Some of the drug companies have walked away from amyloid, but others persist. In Eli Lilly's study about 20 percent of the trial participants had the symptoms of Alzheimer's disease but no detectable amyloid, so Eli just removed them from their future trial. Many reasons can be given for the lackluster results produced by anti-amyloid drugs: oligomers are more toxic than plaques, the drugs were not given soon enough, it is hard to detect amyloid, the drugs did not get into the brain, they did not lower amyloid levels sufficiently enough, etc. But the most likely explanation is that while amyloid may contribute to Alzheimer's disease it is not the cause. Amyloid may contribute to the production of peroxynitrites, but if you remove amyloid, the damage done by peroxynitrites remains and peroxynitrites continue to form (albeit at perhaps a slower rate).

A number of scientists are working on peroxynitrite scavengers to treat Alzheimer's disease (curcumin and ferulic acid derivatives, for instance). And there are pharmaceutical companies that are trying to develop peroxynitrite scavengers to treat a variety of diseases. I have contacted both and received different levels of interest and response. To pursue this beyond the level of individual researchers likely requires extraordinary evidence to go forward and while the evidence that peroxynitrite scavengers can help treat Alzheimer's disease is strong it is not extraordinary. Second one would have to be convinced that a synthetic peroxynitrite scavenger would be more effective than a natural peroxynitrite scavenger and so far I have found only one article that claims this. So I am left to make my case in a variety of public forums (to the aggravation of many), presenting a slew of clinical trials, research studies, and case studies indicating that it is at least worth considering the possibility that peroxynitrite scavengers can be used to treat Alzheimer's disease.

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59. Anonymous on December 20, 2013 8:41 AM writes...

Lane, the question is, are they *just* peroxynitrite scavengers? Basically these are all just antioxidants, and will react with any radical/reactive oxygen species. The clinic is littered with the corpses of antioxidant trials that failed to meet endpoints. I see no reason to assume, based on the evidence you insist on supplying - or indeed any other evidence - that peroxynitrite scavenging will fare any better.

Permalink to Comment

60. Lane Simonian on December 21, 2013 7:25 PM writes...

This is a very good point. Very few of them are just peroxynitrite scavengers. Many of them scavenge superoxide anions and hydrogen peroxide, inhibit the formation of inducible nitric oxide, upregulate antioxidant enzymes, and act as metal chelators.

Here are some of the knocks on methoxyphenols: curcumin does not enter the bloodstream well, ferulic acid does not enter the brain well, and eugenol can increase agitation in some Alzheimer's patients. Using a combination of these methoxyphenols or developing better synthetic versions of them may offer an effective strategy against Alzheimer's disease.

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