36 replies to this topic

[Elus]

Cancer drug reverses Alzheimer's disease in mice: Hope for humans?

Article Link: http://www.cbsnews.c...ope-for-humans/

(CBS) A new study of a promising Alzheimer's treatment has doctors buzzing that the drug may reverse the deadly neurodegenerative disease. But the new treatment isn't a new drug at all, rather a skin cancer pill that's been FDA-approved for more than a decade.

The drug, bexarotene, reversed signs of Alzheimer's in mice brains and also improved their memory in as little as 72 hours, according to the study.

"This is an unprecedented finding," study author Paige Cramer, a PhD candidate at Case Western Reserve School of Medicine, said in a university written statement. "Previously, the best existing treatment for Alzheimer's disease in mice required several months to reduce plaque in the brain."

Bexarotene - sold under the brand name Targretin - was approved by the FDA in 1999 for treating cutaneous T-cell lymphoma, a cancer of the white blood cells that primarily affects the skin. But the drug also happens to switch on a gene that makes a naturally occurring protein in the brain called Apolipoprotein E, or ApoE.

Previous research by study co-author Dr. Gary Landreth, a professor of neurosciences at Case Western Reserve, showed that ApoE could help facilitate the removal of amyloid beta proteins, which are a toxic substance in the brain that causes plaque buildup that's a marker for Alzheimer's.

Dr. Landreth and his grad student, Cramer, thought if they could use this drug to increase ApoE, then maybe they could reduce some of the plaques in mice that were genetically bred to have Alzheimer's. The researchers found that the drug caused a 50 percent reduction in the amount of amyloid plaques within only three days, and after 14 days, they saw a 75 percent reduction. The drug essentially "reprogrammed" the brain's immune cells to "eat" the amyloid plaques.

The brain plaque reduction was also associated with improvements in the rat's behavior. Mice instinctively make nests out of materials around them, but mice with Alzheimer's typically fail this task. But after 72 hours of bexarotene treatment, the Alzheimer's mice could build nests from tissue paper, and also performed better on other tests, which suggest a "clearer thought process," Cramer said in a university video.

The study is published in the Feb. 9 issue of the journal, Science.

One caveat to the study - mice aren't people. Despite how promising the findings may seem, the researchers tempered expectations.
"I want to say as loudly and clearly as possible that this was a study in mice, not in humans," Landreth told CNN. "We've fixed Alzheimer's in mice lots of times, so we need to move forward expeditiously but cautiously."

Dr. Maria C. Carrillo, director of scientific relations at the Alzheimer's Association agreed and told the Washington Post, "We need to be cautiously optimistic and pursue this lead as we would any other." But she added, "This an exciting study is that it involves a repurposed drug."

The researchers hope to get approval to study bexarotene in humans as soon as possible, and Landreth told the Post there's an urgency since he's heard from other doctors that patients are already asking about bexarotene.

"We've got to work fast, and we have got to be right," Landreth said. "We can't screw this up."

Alzheimer's is the sixth leading cause of death in the U.S., according to the CDC, taking more than 83,000 lives this past year. More than 5 million people already have Alzheimer's or related dementia, a number that is expected to more than double by 2050 because of the aging population, according to the Alzheimer's Association.

http://www.youtube.com/watch?v=HdYdYeNAYpU

Science Paper:

http://www.sciencema...science.1217697

ABSTRACT

Alzheimer's disease is associated with impaired clearance of β-amyloid from the brain, a process normally facilitated by apolipoprotein E (ApoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator activated receptor (PPARγ) and liver X receptors (LXR) in coordination with retinoid X receptors (RXR). Oral administration of the RXR agonist, bexarotene, to a murine model of Alzheimer's disease resulted in enhanced clearance of soluble Aβ within hours in an apoE-dependent manner. Aβ plaque area was reduced >50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, RXR activation stimulates physiological Aβ clearance mechanisms, resulting in the very rapid reversal of a broad range of Aβ-induced deficits.

Edited by Elus, 10 February 2012 - 08:17 PM.

[Elus]

I just thought I would comment... It's interesting that they upregulated ApoE. In many cases, mutations in ApoE (specifically ApoE-E4), can be a strong genetic indicator/predictor of Alzheimer's disease itself. Because of this, upregulating a non-functional version of ApoE in humans may not lead to the clearance seen with these mice. I myself am ApoE-E4/E3, so someone like me may only get partial benefit. Someone homozygous for ApoE-E4 may receive no benefit from taking bexarotene at all.

However, imagine that we were to inject ApoE-E3 protein into patients who are deficient in that protein. Would that cause a strong, lethal immune response, or would it merely clear plaques as intended? I do not know (If someone can comment, that would be appreciated).

Furthermore, the mouse model they used to simulate Alzheimer's is based on induction of plaque formation via mutating the amyloid beta precursor protein (APP). I'm not sure how relevant this model is to humans (dont have time atm, but didn't michael rae say something here: http://sens.org/node/2577).

We also don't know for sure if amyloid plaques are the cause of Alzheimer's itself or merely a byproduct of some other cause.

This is a great article examining the scientific paper and the questions it raises: http://www.scientifi...-disease-sympto

Nevertheless, exciting stuff.

Edited by Elus, 10 February 2012 - 08:48 PM.

[MrHappy]

I think the plaques are a byproduct of L-arginine depletion by replication of a common envelope virus, HSV-1.

L-arginine normally prevents protein aggregation and is synthesised directly in the brain.

[tunt01]

However, imagine that we were to inject ApoE-E3 protein into patients who are deficient in that protein. Would that cause a strong, lethal immune response, or would it merely clear plaques as intended? I do not know (If someone can comment, that would be appreciated).

http://www.cognosci....y.html#cognoapo

bunch of companies are working on exactly this sort of therapy model... obviously in a novel, patent-worthy approach.

[AgeVivo]

I think the plaques are a byproduct of L-arginine depletion by replication of a common envelope virus, HSV-1.

L-arginine normally prevents protein aggregation and is synthesised directly in the brain.

You express smthg very different from what is often said. Just by curiosity, are you working on this? or it is the result of a personal literature investigation? If so, could be interesting to have such a review.

[MrHappy]

Well, the hypothesis has been around for a few years now. I've also been conducting a small statistically insignificant study (n=5) with some interesting results so far, amongst some family and friends.

There's a list of citations in a post I made here some time back: http://www.longecity...-the-brain-and/

[Lufega]

I think the plaques are a byproduct of L-arginine depletion by replication of a common envelope virus, HSV-1.

L-arginine normally prevents protein aggregation and is synthesised directly in the brain.

You express smthg very different from what is often said. Just by curiosity, are you working on this? or it is the result of a personal literature investigation? If so, could be interesting to have such a review.

If you go on pubmed, you'll find many references to that. Arginine inhibits protein aggregation so there is some truth to what he is saying.

Inhibition of protein aggregation: supramolecular assemblies of arginine hold the key.

Abstract

BACKGROUND:

Aggregation of unfolded proteins occurs mainly through the exposed hydrophobic surfaces. Any mechanism of inhibition of this aggregation should explain the prevention of these hydrophobic interactions. Though arginine is prevalently used as an aggregation suppressor, its mechanism of action is not clearly understood. We propose a mechanism based on the hydrophobic interactions of arginine.

Arginine increases the solubility of Abeta(1-42) peptide in aqueous medium. It decreases the aggregation of Abeta(1-42) as observed by atomic force microscopy.

CONCLUSIONS:

Based on our experimental results we propose that molecular clusters of arginine in aqueous solutions display a hydrophobic surface by the alignment of its three methylene groups. The hydrophobic surfaces present on the proteins interact with the hydrophobic surface presented by the arginine clusters. The masking of hydrophobic surface inhibits protein-protein aggregation. This mechanism is also responsible for the hydrotropic effect of arginine on various compounds. It is also explained why other amino acids fail to inhibit the protein aggregation.

PDF http://www.ncbi.nlm....one.0001176.pdf

Although, I don't think Arginine would perform as spectacularly as this medication. However, the downstream effect of APOe activation by said drug, is the activation of an arginine dependent system. The patent for this drug expires in 2016, I think so we probably wont be hearing much about this again. Can't wait to self-experiment with generics. It seems even healthy people accumulate amyloid at the cost of some cognitive functions...

[MrHappy]

The drug could be a panacea.

Supplementing L-arginine won't help much, as although you are helping to prevent protein clumping, you're fueling the virus and potentially hastening the progress of the disease. Better to kill the virus.

[revenant]

Incredible findings regarding the Bexarotene. Thanks Elus. We can only hope this can be put to clinical use soon for those in need.

It could be possible that other viral agents besides HSV1 deplete l-arginine. Targeted reverse transcriptase inhibitors may help with AD?

[mag1]

I am unclear when Bexarotene loses patent protection. In some media reports it was reported that patent protection would be lost in April of this year, though there is also reference to 2015 and 2016.
When will generic Bexarotene be available?

[Elus]

I am unclear when Bexarotene loses patent protection. In some media reports it was reported that patent protection would be lost in April of this year, though there is also reference to 2015 and 2016.
When will generic Bexarotene be available?

Hi Mag1,

I saw you've recently posted that you are you suffering from Alzheimer's dementia. My hope is that this drug may eventually help people who are suffering from AD. However, it's unclear if this drug will work in human as it does in mice. Furthermore, humans are polymorphic for ApoE. This means that someone who has a mutated ApoE gene, like myself, may not benefit from taking the drug at all. If you've had a genome scan, you may know your ApoE status, which could be relevant in this case.

I would just advise caution if you manage to somehow obtain Bexarotene. I also realize time is of the essence, so please let us know how you're doing..

Best wishes,
Elus

Edited by Elus, 12 February 2012 - 06:06 PM.

[mag1]

I have been genotyped APOE epsilon 33, with an APOE promoter polymorphism, and a very favourable tau genotype.

Given the recent Bexarotene research, I am not clear how my APOE promoter polymorphism could increase my risk of dementia,
given my epsilon 33 genotype. I would have thought that the new research would imply that more epsilon 33 for me would result in
less amyloid.

Needless to say, I am very interested in the Bexarotene research. I intend to contact my doctor and ask for a prescription for Bexarotene.
I think it is reasonable to try a few doses of it. The human equivalent dose used in the Bexarotene research is, for me, only equal to the dose that
I would be prescribed if I were a cancer patient. This does raise questions for me, though. How could so many older people (many with dementia)
have taken Bexarotene for so long and not noticed that their Alzheimer's had disappeared? Could APOE genotype have obscured the benefits?
The results in the mice were so compelling and the drug has been used for so long that I feel comfortable giving it a limited trial. I think it would be
best, though, to see what the early adopters can discover first.

It is very exciting that Bexarotene is only the first attempt to modify this specific pathway. Apparently, more powerful RXRs have already been developed. For example a
selective RXR alpha agonist has been created. Bexarotene is an agonist for alpha, beta and gamma types of RXR, and there are two subtypes for each of the types.
It would be very interesting to see how the Alzheimer mice responded to each of the RXR subtypes. If I have trouble obtaining a prescription, perhaps I could try high dose DHA
which is another RXR agonist.

I am now beginning to struggle performing basic activities of daily living, so any improvement would be such a blessing.

Thank you for your kind words!

Edited by mag1, 12 February 2012 - 06:46 PM.

[Lufega]

What I find interesting is that Bexarotene is yet another derivative of vitamin A, more specifically, a third generation retinoid. On one end, they tell us to avoid animal forms of vitamin A for the horrid toxicity. On the other, these derivatives have therapeutic effects on all kinds of condition from acne to cancer. So, does dietary retinol have any effect on amyloid formation and Alzheimer's disease ? This is what a quick look turned up.

Bexarotene is a retinoid specifically selective for retinoid X receptors, as opposed to the retinoic acid receptors.

Vitamin A enhances in vitro Th2 development via retinoid X receptor pathway. PMID:11970994

Vitamin A and Alzheimer's disease.

Abstract

The deposition of amyloid β-protein (Aβ) in the brain is an invariant feature of Alzheimer's disease (AD). Vitamin A, which has been traditionally considered an anti-oxidant compound, plays a role in maintaining higher function in the central nervous system. Plasma or cerebrospinal fluid concentrations of vitamin A and β-carotene have been reported to be lower in AD patients, and these vitamins have been clinically shown to slow the progression of dementia. Vitamin A (retinol, retinal and retinoic acid) and β-carotene have been shown in in vitro studies to inhibit the formation, extension and destabilizing effects of β-amyloid fibrils. Recently, the inhibition of the oligomerization of Aβ has been suggested as a possible therapeutic target for the treatment of AD. We have recently shown the inhibitory effects of vitamin A and β-carotene on the oligomerization of Aβ40 and Aβ42 in vitro. In previous in vivo studies, intraperitoneal injections of vitamin A decreased brain Aβ deposition and tau phosphorylation in transgenic mouse models of AD, attenuated neuronal degeneration, and improved spatial learning and memory. Thus, vitamin A and β-carotene could be key molecules for the prevention and therapy of AD. Geriatr Gerontol Int 2011; ••: ••-••.
© 2011 Japan Geriatrics Society. PMID:22221326 [PubMed - as supplied by publisher]

Vitamin A has anti-oligomerization effects on amyloid-β in vitro.

Abstract

Inhibition of amyloid-β (Aβ) aggregation is an attractive therapeutic strategy for treatment of Alzheimer's disease (AD). We previously reported that vitamin A and β-carotene inhibit fibrillation of Aβ40 and Aβ42 (Ono et al, 2004, Exp Neurol). In this study, we firstly examined the effects of vitamin A (retinoic acid, retinol, and retinal), β-carotene, vitamin B2, vitamin B6, vitamin C, vitamin E, coenzyme Q10, and α-lipoic acid on oligomerization of Aβ40 and Aβ42 in vitro; vitamin A and β-carotene dose-dependently inhibited oligomerization of Aβ40 and Aβ42. Furthermore, retinoic acid decreased cellular toxicity by inhibition of Aβ42 oligomerization. Second, we analyzed how vitamin A inhibits Aβ aggregation by using fluorescence spectroscopy and thioflavin T assay with two Aβ fragments, Aβ1-16 and Aβ25-35. A fluorescence peak of retinoic acid was greatly restrained in the presence of Aβ25-35, and retinoic acid inhibited aggregation of Aβ25-35, but not of Aβ1-16, which suggest the specific binding of retinoic acid to the C-terminal portion of Aβ. Thus, vitamin A and β-carotene might be key molecules for prevention of AD.

PMID: 21811022 [PubMed - in process]

Retinoic acid normalizes nuclear receptor mediated hypo-expression of proteins involved in beta-amyloid deposits in the cerebral cortex of vitamin A deprived rats.

Abstract

Recent data have revealed that disruption of vitamin A signaling observed in Alzheimer's disease (AD) leads to a deposition of beta-amyloid (Abeta). The aim of this study was to precise the role of vitamin A and its nuclear receptors (RAR) in the processes leading to the Abeta deposits. Thus, the effect of vitamin A depletion and subsequent administration of retinoic acid (RA, the active metabolite of vitamin A ) on the expression of RARbeta, and of proteins involved in amyloidogenic pathway, e.g., amyloid precursor protein (APP), beta-secretase enzyme (BACE), and APP carboxy-terminal fragment (APP-CTF) was examined in the whole brain, hippocampus, striatum, and cerebral cortex of rats. Rats fed a vitamin A -deprived diet for 13 weeks exhibited decreased amount of RARbeta, APP695, BACE, and of APP-CTF in the whole brain and in the cerebral cortex. Administration of RA is able to restore all expression. The results suggest that fine regulation of vitamin A mediated gene expression seems fundamental for the regulation of APP processing.

Vitamin A exhibits potent antiamyloidogenic and fibril-destabilizing effects in vitro.

Abstract

Cerebral deposition of amyloid beta-peptide (Abeta) in the brain is an invariant feature of Alzheimer disease (AD). Plasma or cerebrospinal fluid concentrations of antioxidant vitamins and carotenoids, such as vitamins A, C, E, and beta-carotene, have been reported to be lower in AD patients, and these vitamins clinically have been demonstrated to slow the progression of dementia. In this study, we used fluorescence spectroscopy with thioflavin T (ThT) and electron microscopy to examine the effects of vitamin A (retinol, retinal, and retinoic acid), beta-carotene, and vitamins B2, B6, C, and E on the formation, extension, and destabilization of beta-amyloid fibrils (fAbeta) in vitro. Among them, vitamin A and beta-carotene dose-dependently inhibited formation of fAbeta from fresh Abeta, as well as their extension. Moreover, they dose-dependently destabilized preformed fAbetas. The overall activity of the molecules examined was in the order of retinol = retinal > beta-carotene > retinoic acid. Although the exact mechanisms are still unclear, vitamins A and beta-carotene could be key molecules for the prevention and therapy of AD.

Lastly, thyroid function, which seems to be involved in everything !

Thyroid hormone regulates endogenous amyloid-beta precursor protein gene expression and processing in both in vitro and in vivo models.

Abstract

Thyroid hormone negatively regulates the amyloid -beta precursor protein (APP) gene in thyroid hormone receptor (TR)-transfected neuroblastoma cells. A negative thyroid hormone response element (nTRE) that mediates this regulation has been identified in the first exon of the APP gene. We demonstrate in an in vivo system that expression of APP mRNA, APP protein, and APP secretase cleavage products in mouse brain is influenced by thyroid status. Adult female mice were made hyperthyroid or hypothyroid for 3 weeks and compared to euthyroid mice. APP gene product expression was increased in hypothyroid mouse brain and reduced in hyperthyroid mouse brain, when compared to euthyroid controls. We observed similar effects of thyroid hormone on endogenous APP gene expression in human neuroblastoma cells.

The incidence of hypothyroidism increases with age, and localized hypothyroidism of central nervous system has been reported in some patients with Alzheimer's disease (AD). Reduced action of thyroid hormone on the APP gene may contribute to AD pathology by increasing APP expression and the levels of processed APP products.

These findings may be an underlying mechanism contributing to the association of hypothyroidism with AD in the elderly, as well as identifying a potential therapeutic target.

Pharmacologic supplementation of thyroid hormone, or its analogs, may reduce APP gene expression and beta amyloid peptide accumulation.

Edited by Lufega, 12 February 2012 - 08:03 PM.

[Elus]

I have been genotyped APOE epsilon 33, with an APOE promoter polymorphism, and a very favourable tau genotype.

Given the recent Bexarotene research, I am not clear how my APOE promoter polymorphism could increase my risk of dementia,
given my epsilon 33 genotype. I would have thought that the new research would imply that more epsilon 33 for me would result in
less amyloid.

Bexarotene causes increased production of the ApoE protein. However, if mutated ApoE-4 is produced, then it may not do its job correctly. It won't clean up the plaques. So before you start inducing more production of ApoE, it's best to check that you're not inducing a mutated version rather than the correct one.

Still, this is just a hunch and maybe one could even get results with the ApoE-4 copy. Or maybe neither would bring results. It's just hard to tell at this point.

[niner]

I have been genotyped APOE epsilon 33, with an APOE promoter polymorphism, and a very favourable tau genotype.

Given the recent Bexarotene research, I am not clear how my APOE promoter polymorphism could increase my risk of dementia, given my epsilon 33 genotype. I would have thought that the new research would imply that more epsilon 33 for me would result in less amyloid.

Needless to say, I am very interested in the Bexarotene research. I intend to contact my doctor and ask for a prescription for Bexarotene. I think it is reasonable to try a few doses of it. The human equivalent dose used in the Bexarotene research is, for me, only equal to the dose that I would be prescribed if I were a cancer patient. This does raise questions for me, though. How could so many older people (many with dementia) have taken Bexarotene for so long and not noticed that their Alzheimer's had disappeared? Could APOE genotype have obscured the benefits?
The results in the mice were so compelling and the drug has been used for so long that I feel comfortable giving it a limited trial. I think it would be best, though, to see what the early adopters can discover first.

It is very exciting that Bexarotene is only the first attempt to modify this specific pathway. Apparently, more powerful RXRs have already been developed. For example a selective RXR alpha agonist has been created. Bexarotene is an agonist for alpha, beta and gamma types of RXR, and there are two subtypes for each of the types. It would be very interesting to see how the Alzheimer mice responded to each of the RXR subtypes. If I have trouble obtaining a prescription, perhaps I could try high dose DHA
which is another RXR agonist.

I am now beginning to struggle performing basic activities of daily living, so any improvement would be such a blessing.

The ApoE 33 genotype is the "good one" for AD, so I wouldn't worry about that. The point you bring up about why no one has seen this effect in cancer patients who also have AD is a good one. I can offer a couple of reasons. First, this is a second or third line drug, and really isn't used very much. I heard the other day that only 2000 prescriptions were written for it last year. Secondly, there probably are few if any people with frank AD that have gotten this drug. People with mild or subclinical AD who got the drug could have improved without connecting it to the use of the drug. Patients who had advanced AD might have gone to hospice instead of pursuing multiple rounds of chemotherapy.

If I were facing dementia, I would seek out this drug and take it. There is a significant list of side effects, including high likelihood of hyperlipidemia, hypercholesterolemia, and hypothyroidism, among other things. All of these are manageable, but will require monitoring.

It is not yet known what an optimal dosing strategy would be. In an interview on TOTN Science Friday, the PI on the paper said that they had given the mice more than was necessary, which is typical for early work. I would imagine that reports will be filtering into AD forums and online communities relatively soon regarding peoples' experience with it. If you try this, please keep us posted.

[MrHappy]

So next question for the brave or with nothing to lose.. cost.

Bexarotene (non-human consumption) is not that expensive:
http://www.lclabs.co...A-C/B-2422.php4

Targretin is expensive! This is one of the cheapest online resellers I've seen so far:
http://www.cheap-can...exarotene_.html

If you were really curious, there are *many* manufacturers in Asia selling direct on the web. No pricing information listed - email enquiry required.
http://www.vvchem.co...-0,2616151.html
http://www.scccorpor...ilpro.php?id=17

[niner]

Bexarotene (non-human consumption) is not that expensive:
http://www.lclabs.co...A-C/B-2422.php4

Targretin is expensive! This is one of the cheapest online resellers I've seen so far:
http://www.cheap-can...exarotene_.html

The non human stuff is surprisingly close to the Canadian Pharmacy version:
"Non human" $305/g (in 5g quantity)
"human" $370/g

Obviously, both of these are very high profit items. If a doctor writes an off-label prescription, expensive insurance plans might cover it. Others might not.

[choqueiro]

I´m really excited with this news. I´m not an expert in the matter but I´m curious about one aspect. It is said that AD appears 30 years before the first symptoms appear (see: http://www.medicinen...rticlekey=53642). If bexarotene fights with efficiency against AD (let´s hope) maybe it could be a must supplement at an early age. The problem is how to identify a futuire AD 30 years before?? It is possible?? Little memory issues at an early age could be a symptom of a future AD?? In that case how we can distinguish a memory issue caused for a premature AD of those caused by other pathologies?? (memory issues are a symptom of many pathologies).

[MrHappy]

If anyone is tempted, I'll check the FOB pricing from China.. last time I ordered some nootropics, it was at least 10x cheaper.. and that wasn't a 'high-margin' product. I can only wonder what this would cost direct from the manufacturer...

[mag1]

I have been considering the story about the Bexarotene for a few days and I am still perplexed by it.

It is still a mystery to me how dementia patients could have received Bexarotene and might have been instantly cured of dementing illness without anyone noticing this.
The median age reported for the skin cancer patients receiving Bexarotene was over 60. Almost everyone who lives to 80 will have some burden of neurodegenerative
illness. By their mid-80s, almost half will have clinical Alzheimer's, and many of the other half will have amyloid/tau pathology. An overwhelming number of the cancer patients
must have had cognitive issues, mild cognitive impairment or clinical Alzheimer's disease. It is beyond my comprehension how if the Bexarotene actually worked,
that no one had ever realized it. If I could instantly improve my MMSE score 20 or more points, my entire lifetime network of friends and family all over the world would become
aware of this within hours.

My family is constantly trying nutritional treatments on me (e.g. turmeric, EGCG, etc.) and assessing my cognitive response. Some of these supplements have made a difference
for me, though often the benefit is modest and temporary. The families of many Alzheimer's patients are very conscious of changes in the cognitive ability of their loved ones.
As the illness progress, even slight reductions in cognitive ability of patients can result in significant increases in care giving effort. How could large changes in cognition have
been ignored by so many people?

Could cancer doctors actually have routinely prescribed Bexarotene to patients over many years and not have realized that patients were being cured of dementia?
Is it conceivable that trained professionals could be so oblivious?

There are some plausible explanations for not noticing dramatic Bexarotene treatment effects: perhaps there have not been any. Simply reducing amyloid levels after
clinical dementia has been established might not lead to profound cognitive improvement. Alternatively, the other cancer drugs could have prevented any benefit, the Bexarotene
dosing might not have been optimal, the immune systems of the patients might have been compromised by chemotherapy treatments etc. There is also research that suggests that
Alzheimer patients are protected against cancer. Over the years, I have had several very large growths removed from my digestive system. After the surgeries I have never required
any chemotherapy or additional treatments. The Bexarotene research was presented to the scientific community 8 months ago, so they have had time to do the initial rounds of confirming
the research and the researchers must be confident in it.

There have been other treatments for Alzheimer's that have eluded attention, yet they have had subtler benefits. Most of the other treatments have only slowed or stopped progression.
Methylene Blue halted the progression of Alzheimer dementia during a year and a half treatment period. The scientific community had been unaware of the dementia treatment potential
of Methylene Blue, even though it had been on the market for over 100 years.

It is also surprising to me that Bexarotene has not caught the attention of the pharmaceutical industry until now. PPAR agonists have been investigated in Alzheimer's disease for over 10 years.
Bexarotene has been known to be associated with PPAR chemistry for over 10 years. Should not a biotech company have systematically tried every PPAR agonist to determine their effect on amyloid pathology? It is startling that no company actually did this research.

The American government has recently declared a national Alzheimer emergency, and yet does not require drugs to be tested for their dementiogenic potential.
Does not the recent research with Bexarotene raise important questions about the safety of approved pharmaceuticals? What if increasing APOE levels had increased the risk for dementia for
everyone. It is still not known what effects Bexarotene will have in APOE epsilon 4s. It is troubling to know that Bexarotene has been clinically tested to treat hair loss without knowing what
risk it might pose for Alzheimer's dementia.

It is projected that if the Alzheimer crisis is not resolved, the cost to manage the problem in America could exceed $1,000,000,000,000 per year and would likely bankrupt the American health care system. Would it not be sensible to systematically research FDA approved medications for their Alzheimer treatment potential? Several promising treatments for Alzheimer's have been discovered among already approved medications, including Methylene Blue, Leukine, clioquinol, IVIG, Etanercept, and Bexarotene. There might be many more. Everyone should be interested in knowing which approved drugs cause dementing illness. Every drug that is brought to market goes through a lengthy screen for carcinogenicity because people are profoundly concerned about cancer risk. I do not understand why people are not also profoundly concerned about their dementia risk.

[AIGuy]

It may be that the standard dosage of Bexarotene given for cancer is less than that given to mice to cause the reversal in plaque/tau buildup.

That would be an explanation for not noticing the effect on patients that have both Alzheimers and Cancer and are being treated with Bexarotene.

So the question is if you scale the Bexarotene dosage based on the body weight a the mouse, what dosage would that be equivilent to for a human. And at that dosage level, what is the toxicity to humans?

It may require a smaller dosage than is given for cancer or a far larger one.

If it is smaller or larger people should be informed because people will be self-medicating and if they're taking more than is required they could be exposing themselves to far greater risk of side effects.

And if they are under dosing they may be just spending a lot of money without crossing the threshhold that the mice did to clear the plaque.

I believe that when a drug is approved the drug companies must provide the amount at which the drug becomes toxic in case of accidental overdose but since many Cancer drugs are somewhat toxic and kill healthy cells as well I'm not sure that the dosage given now for Cancer would not be considered to be toxic and how much it could incrase by without damging major organs or causing death.

[Musli]

As far as I know amyloid beta plaques don't cause AD. Hell, removing them helps improve brain function only a bit. I believe removing the tangles made up of tau proteins turned out to be a more effective strategy for improving brain function in elderly, so don't expect too much from this drug, and amyloid beta removal in general.

Edited by Musli, 22 February 2012 - 01:09 AM.

[AIGuy]

Musli,

The paper did say that mouse testable signs of mental deterioration were reversed.

Wouldn't that indicate that if the Tau protein was the cause of the mental deterioration and that it was removed along with the amyloid plaques?

Are there other studies that show removing beta plaques do not improve brain function in the elderly?

Has that been confirmed by autopsy?

Or is there autopsy evidence of severe Alzheimer's disease with no amyloid beta plaques build up?

I'm not disagreeing just trying to understand.

[Musli]

AIGuy, look for ex. here: http://www.soton.ac....ul/08_140.shtml
What's more, I think I also heard about it in a video from SENS5 conference focused mainly on the clearance of tau protein -

[Elus]

New development on the Parkinson's Front: http://www.scienceda...20302101417.htm


Parkinson's Disease Stopped in Animal Model: Molecular 'Tweezers' Break Up Toxic Aggregations of Proteins

Millions of people suffer from Parkinson's disease, a disorder of the nervous system that affects movement and worsens over time. As the world's population ages, it's estimated that the number of people with the disease will rise sharply. Yet despite several effective therapies that treat Parkinson's symptoms, nothing slows its progression.

Now, scientists at UCLA have found a way to prevent these clumps from forming, prevent their toxicity and even break up existing aggregates.While it's not known what exactly causes the disease, evidence points to one particular culprit: a protein called α-synuclein. The protein, which has been found to be common to all patients with Parkinson's, is thought to be a pathway to the disease when it binds together in "clumps," or aggregates, and becomes toxic, killing the brain's neurons.

UCLA professor of neurology Jeff Bronstein and UCLA associate professor of neurology Gal Bitan, along with their colleagues, report the development of a novel compound known as a "molecular tweezer," which in a living animal model blocked α-synuclein aggregates from forming, stopped the aggregates' toxicity and, further, reversed aggregates in the brain that had already formed. And the tweezers accomplished this without interfering with normal brain function.

The research appears in the current online edition of the journal Neurotherapeutics.

There are currently more than 30 diseases with no cure that are caused by protein aggregation and the resulting toxicity to the brain or other organs, including Parkinson's, Alzheimer's and Type 2 diabetes. It is therefore critical, Bronstein said, to find a way to stop this aggregation process. Over the last two decades, researchers and pharmaceutical companies have attempted to develop drugs that would prevent abnormal protein aggregation, but so far, they have had little or no success.

While these aggregates are a natural target for a drug, finding a therapy that targets only the aggregates is a complicated process, Bronstein said. In Parkinson's, for example, the protein implicated in the disorder, α-synuclein, is naturally ubiquitous throughout the brain.

"Its normal function is not well understood, but it may play a role in aiding communication between neurons," Bronstein said. "The trick, then, is to prevent the α-synuclein protein aggregates and their toxicity without destroying α-synuclein's normal function, along with, of course, other healthy areas of the brain.

Molecular tweezer

Bronstein collaborated with Bitan, who had been working with a particular molecular tweezer he had developed called CLR01. Molecular tweezers are complex molecular compounds that are capable of binding to other proteins. Shaped like the letter "C," these compounds wrap around chains of lysine, a basic amino acid that is a constituent of most proteins.

Working first in cell cultures, the researchers found that CLR01 was able to prevent α-synuclein from forming aggregates, prevent toxicity and even break up existing aggregates.

"The most surprising aspect of the work," Bronstein said, "is that despite the ability of the compound to bind to many proteins, it did not show toxicity or side effects to normal, functioning brain cells."

"We call this unique mechanism 'process-specific,' rather than the common protein-specific inhibition," Bitan added, meaning the compound only attacked the targeted aggregates and nothing else.

The researchers next tried their tweezers in a living animal, the zebrafish, a tropical freshwater fish commonly found in aquariums. The zebrafish is a popular animal for research because it is easily manipulated genetically, develops rapidly and is transparent, making the measurement of biological processes easier.

Using a transgenic zebrafish model for Parkinson's disease, the researchers added CLR01 and used fluorescent proteins to track the tweezer's effect on the aggregations. They found that, just as in cell cultures, CLR01 prevented α-synuclein aggregation and neuronal death, thus stopping the progression of the disorder in the living animal model.

Being able to prevent α-synuclein from aggregating, prevent toxicity and break up existing aggregates is a very encouraging result, but still, at the end of the day, "we've only stopped Parkinson's in zebrafish," Bronstein said.

"Nonetheless," he said, "all of these benefits of CLR01 were found without any evidence of toxicity. And taken together, CLR01 holds great promise as a new drug that can slow or stop the progression of Parkinson's and related disorders. This takes us one step closer to a cure."

The researchers are already studying CLR01 in a mouse model of Parkinson's and say they hope this will lead to human clinical trials.

Other authors of the study included Shubhangi Prabhudesai, Sharmistha Sinha, Aida Attar, Aswani Kotagiri, Arthur G. Fitzmaurice, Ravi Lakshmanan, Magdalena I. Ivanova, Joseph A. Loo and Mark Stahl, all of UCLA, and Frank-Gerrit Klärner and Thomas Schrader of the University of Duisburg-Essen in Germany.

Funding was provided by multiple sources, including the Levine Foundation, the American Health Assistance Foundation, the UCLA Jim Easton Consortium for Alzheimer's Drug Discovery and Biomarker Development, the Team Parkinson/Parkinson Alliance, and the National Institutes of Health.

Edited by Elus, 03 March 2012 - 08:57 AM.

[niner]

There are currently more than 30 diseases with no cure that are caused by protein aggregation and the resulting toxicity to the brain or other organs, including Parkinson's, Alzheimer's and Type 2 diabetes.

T2D is caused by protein aggregation? Really?

[Elus]

There are currently more than 30 diseases with no cure that are caused by protein aggregation and the resulting toxicity to the brain or other organs, including Parkinson's, Alzheimer's and Type 2 diabetes.

T2D is caused by protein aggregation? Really?

Did a quick google search and some stuff came up: http://www.nasw.org/...etesProtein.htm

[niner]

Well, ya learn something new every day. A pubmed search on diabetes and amyloid gets ~2K hits. Interestingly, this was the very first hit:

Biochem Biophys Res Commun. 2012 Feb 14. [Epub ahead of print]
Silibinin inhibits the toxic aggregation of human islet amyloid polypeptide.
Cheng B, Gong H, Li X, Sun Y, Zhang X, Chen H, Liu X, Zheng L, Huang K.

Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China.

In type 2 diabetes mellitus (T2DM), misfolded human islet amyloid polypeptide (hIAPP) forms amyloid deposits in pancreatic islets. These amyloid deposits contribute to the dysfunction of β-cells and the loss of β-cell mass in T2DM patients. Inhibition of hIAPP fibrillization has been regarded as a potential therapeutic approach for T2DM. Silibinin, a major active flavonoid extracted from herb milk thistle (Silybum marianum), has been used for centuries to treat diabetes in Asia and Europe with unclear mechanisms. In this study, we tested whether silibinin has any effect on the amyloidogenicity of hIAPP. Our results provide first evidence that silibinin inhibits hIAPP fibrillization via suppressing the toxic oligomerization of hIAPP and enhances the viability of pancreatic β-cells, therefore silibinin may serve as a potential therapeutic agent for T2DM.

PMID: 22366091

The following is a review with free text.

Exp Diabetes Res. 2008;2008:421287.
Recent insights in islet amyloid polypeptide-induced membrane disruption and its role in beta-cell death in type 2 diabetes mellitus.
Khemtémourian L, Killian JA, Höppener JW, Engel MF.

Department of Metabolic and Endocrine Diseases, Division of Biomedical Genetics, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands.

The presence of fibrillar protein deposits (amyloid) of human islet amyloid polypeptide (hIAPP) in the pancreatic islets of Langerhans is thought to be related to death of the insulin-producing islet beta-cells in type 2 diabetes mellitus (DM2). The mechanism of hIAPP-induced beta-cell death is not understood. However, there is growing evidence that hIAPP-induced disruption of beta-cell membranes is the cause of hIAPP cytotoxicity. Amyloid cytotoxicity by membrane damage has not only been suggested for hIAPP, but also for peptides and proteins related to other misfolding diseases, like Alzheimer's disease, Parkinson's disease, and prion diseases. Here we review the interaction of hIAPP with membranes, and discuss recent progress in the field, with a focus on hIAPP structure and on the proposed mechanisms of hIAPP-induced membrane damage in relation to beta-cell death in DM2.

PMID: 18483616

[Picard]

I found this posted in the comments of one article discussing this:

Alfred Berger
February 16th, 2013 - 11:20:22 AM

I am caregiver to my wife who has had Alzheimer's for 12 years. We have done all the clinical trials and a year ago she fell below the Memory tests for more trials. She was going down fast at that time. Just a year ago I heard about the Targretin animal tests for Alzheimer's. She will be on Targretin for a year this April 5th. She tolerates the drug well except for some hair loss. She was on one pill per day until recently when I reduced the dosage to one pill every two days because of costs.
I have noticed significant improvement in her incontenance, her curiousity and function. She is looking at a book as I write this message something that she would not have done before. I find that this drug has been very significant in arresting and partially bring her back. She still has a damaged brain from years of the desease. We cannot hope for complete recovery, but had these studies been done earlier in her desease, I believe that this drug would prevent further deteriation from this dreaded desease. No other drug changes have been made during this time. I am writing this only to inform the concerned professionals.

[Elus]

Well..... damn.


Studies cast doubt on cancer drug as Alzheimer's treatment

http://www.nature.co...eatment-1.13058

Edited by Elus, 24 May 2013 - 04:09 PM.