FDA-approved drug rapidly clears amyloid from the brain, reverses Alzheimer's symptoms in mice

Neuroscientists at Case Western Reserve University School of Medicine have made a dramatic breakthrough in their efforts to find a cure for Alzheimer's disease. The researchers' findings, published in the journal Science, show that use of a drug in mice appears to quickly reverse the pathological, cognitive and memory deficits caused by the onset of Alzheimer's. The results point to the significant potential that the medication, bexarotene, has to help the roughly 5.4 million Americans suffering from the progressive brain disease.

Bexarotene has been approved for the treatment of cancer by the U.S. for more than a decade. These experiments explored whether the medication might also be used to help patients with Alzheimer's disease, and the results were more than promising.

Alzheimer's disease arises in large part from the body's inability to clear naturally-occurring amyloid beta from the brain. In 2008 Case Western Reserve researcher Gary Landreth, PhD, professor of neurosciences, discovered that the main cholesterol carrier in the brain, Apolipoprotein E (ApoE), facilitated the clearance of the . Landreth, a professor of neurosciences in the university's medical school, is the senior author of this study as well.

Landreth and his colleagues chose to explore the effectiveness of bexarotene for increasing ApoE expression. The elevation of brain ApoE levels, in turn, speeds the clearance of amyloid beta from the brain. Bexarotene acts by stimulating retinoid X receptors (RXR), which control how much ApoE is produced.

In particular, the researchers were struck by the speed with which bexarotene improved and behavior even as it also acted to reverse the pathology of Alzheimer's disease. The present view of the scientific community is that small soluble forms of amyloid beta cause the memory impairments seen in animal models and humans with the disease. Within six hours of administering bexarotene, however, soluble amyloid levels fell by 25 percent; even more impressive, the effect lasted as long as three days. Finally, this shift was correlated with rapid improvement in a broad range of behaviors in three different mouse models of Alzheimer's.

One example of the improved behaviors involved the typical nesting instinct of the mice. When Alzheimer's-diseased mice encountered material suited for nesting – in this case, tissue paper – they did nothing to create a space to nest. This reaction demonstrated that they had lost the ability to associate the tissue paper with the opportunity to nest. Just 72 hours after the bexarotene treatment, however, the mice began to use the paper to make nests. Administration of the drug also improved the ability of the mice to sense and respond to odors.

Bexarotene treatment also worked quickly to stimulate the removal of amyloid plaques from the brain. The plaques are compacted aggregates of amyloid that form in the brain and are the pathological hallmark of Alzheimer's disease. Researchers found that more than half of the plaques had been cleared within 72 hours. Ultimately, the reduction totaled 75 percent. It appears that the bexarotene reprogrammed the brain's immune cells to "eat" or phagocytose the amyloid deposits. This observation demonstrated that the drug addresses the amount of both soluble and deposited forms of amyloid beta within the brain and reverses the pathological features of the disease in mice.

This study identifies a link between the primary genetic risk factor for Alzheimer's disease and a potential therapy to address it. Humans have three forms of ApoE: ApoE2, ApoE3, and ApoE4. Possession of the ApoE4 gene greatly increases the likelihood of developing Alzheimer's disease. Previously, the Landreth laboratory had shown that this form of ApoE was impaired in its ability of clear amyloid. The new work suggests that elevation of ApoE levels in the brain may be an effective therapeutic strategy to clear the forms of amyloid associated with impaired memory and cognition.

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

Added Professor Landreth: "This is a particularly exciting and rewarding study because of the new science we have discovered and the potential promise of a therapy for Alzheimer's disease. We need to be clear; the drug works quite well in mouse models of the disease. Our next objective is to ascertain if it acts similarly in humans. We are at an early stage in translating this basic science discovery into a treatment."

Daniel Wesson, PhD, assistant professor of neurosciences at Case Western Reserve School of Medicine and co-author of the study agreed.

"Many often think of Alzheimer's as a problem of remembering and learning, but the prevalent reality is this disease spreads throughout the brain, resulting in serious insults to numerous functions," he said. "The results of this study, showing the preservation of behaviors across a wide spectrum, and accompanying function, are tremendously exciting and suggest great promise in the utility of this approach in treatment of ."

Bexarotene has a good safety and side-effect profile. The Case Western Reserve researchers hope these attributes will help speed the transition to clinical trials of the drug.

Professor Landreth said modest resources funded this self-described "far-fetched idea." Crucial support came from the Blanchette Hooker Rockefeller Foundation, the Thome Foundation, and the National Institutes of Health.

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dogbert
3.7 / 5 (3) Feb 09, 2012
Wow!

Hope this results in human therapy.
Telekinetic
1 / 5 (2) Feb 09, 2012
Curious name, Bexarotene- sounds an awful lot like carotene, the natural vitamin in carrots. So this synthetic drug is stimulating retinoid X receptors which control the levels of ApoE, which in turn clears the amyloid plaque. Considering that this is a potential multi-billion dollar bonanza for drug companies, I'm wondering if they may be making something that nature's already made. Imagine a super-critical form of beta-carotene or analog of it that had the same effect, but the body recognizes more readily than the synthetic, and its cost was much cheaper. Then again, I wouldn't want to take the profit away from the nice pharmaceutical company.
Atherophage
not rated yet Feb 09, 2012
No problems finding eager humans upon which to test this therapy, I'm sure.
Sinister1811
Feb 09, 2012
This comment has been removed by a moderator.
Jaeherys
Feb 09, 2012
This comment has been removed by a moderator.
Jaeherys
not rated yet Feb 09, 2012
On a side note, don't use non-IUPAC names to assume similarities.
Telekinetic
1 / 5 (2) Feb 09, 2012
@Jaeherys:

Betacarotene, a precursor form of vitamin A typical of vegetable sources such as carrots, is selectively converted into retinoids.
On a side note, do a little research before you publish.
Jaeherys
Feb 09, 2012
This comment has been removed by a moderator.
Telekinetic
1 / 5 (2) Feb 09, 2012
" Bexarotene acts by stimulating retinoid X receptors (RXR), which control how much ApoE is produced."- from the article

The natural beta-carotene is converted to a retinoid- which finds its way to retinoid receptors.
Telekinetic
1 / 5 (2) Feb 09, 2012
"bexarotene - Huntsman Cancer Institute - University of Utah
www.hci.utah.edu/....htmlAsk your doctor or pharmacist before taking extra Vitamin A or beta-carotene. Bexarotene is similar to Vitamin A and beta-carotene."
You're a glutton for punishment.
Telekinetic
Feb 09, 2012
This comment has been removed by a moderator.
C_elegans
5 / 5 (1) Feb 10, 2012
You might be on to something, what's the affinity of beta-carotene compared to Bexarotene? How quickly are the two metabolized? A Vitamin A mouse trial may be in order -_-
Telekinetic
Feb 10, 2012
This comment has been removed by a moderator.
Jaeherys
not rated yet Feb 10, 2012
So are you saying they are similar because beta-carotene can be cleaved and go through a few more reactions to give a retinol? Because I can guarantee you, bexarotene and carotene are biochemically very different.

Bexarotene is specific for retinoid X receptors whereas carotene can be a precursor for a retinol which is generic for retinoic acid receptors.

This distinction can clearly be seen just be looking at the two molecules and the products that can be produced from beta-carotene.

Selective binding is the whole point of synthetic versions of natural molecules, typically. Structurally, the selectivity of bexarotene can be see by its functional groups and the fact its not linear.

Just because they might affect the same type of receptor, there are different classes and consequently very different cross talk or second messengers, ect, ect.
Kedas
not rated yet Feb 10, 2012
So this is a drug that can already be bought? (although to treat cancer)

So if you really want and you can find a doctor that 'forgot' that you don't have cancer but alzheimer it can be tried.

Birger
not rated yet Feb 10, 2012
Kedas, I was also wondering how soon this drug can be made available for Alzheimer's patients.
ccr5Delta32
Feb 10, 2012
This comment has been removed by a moderator.
Telekinetic
1 / 5 (2) Feb 10, 2012
@ Jaeherys:
Did you not say?- "bexarotene and carotene are in no way similar."
And later- "That still doesn't make them similar"
I proved you wrong with a warning from a hospital stating- "Bexarotene is similar to Vitamin A and beta-carotene." Initially, I proposed an analog of beta-carotene or a highly concentrated form of carotene itself as a natural alternative. My position is "natural" is a preferred choice over synthetic as there is less likelihood of side effects, and may be equally efficacious. Now be a good sport about it and slink away with your tail between your legs.
Jaeherys
not rated yet Feb 10, 2012
The products of beta-carotene affect the same group of receptors making its products similar to bexarotene. But as I said, bexarotene is target specific and therefore its downstream response will be different.

A direct comparison of beta-carotene and bexarotene shows they are not similar considering one is a signalling molecule and the other is a generic hydrocarbon...

My position is "natural" is a preferred choice over synthetic as there is less likelihood of side effects, and may be equally efficacious


What you are proposing is analogous to comparing methanol and ethanol. Sure both are the same type of molecule but one will kill you.

A warming like you said is a general statement because retinoic acid can have an effect on RARs and RXRs both of which cause DIFFERENT gene expression. This means that bexarotene cannot be directly substituted with a retinoic acid as cross-talk changes relative expressed protein concentrations and by extension cell phenotype.
Jaeherys
not rated yet Feb 10, 2012
You are either just trying to prove you assumption at all costs based on some bias with scientists producing drugs or you have no idea of how signalling molecules actually work.

If beta-carotene could have been used instead, then it would have been published that way.

Putting all that aside, if beta-carotene had the same affect as bexarotene then why do human still get Alzheimer's?

I'm sure their are Alzheimer's patients that eat a lot of carrots and are still sick.

General statements such as your proposition are generally NOT valid.
keris
not rated yet Feb 12, 2012
Maybe you hope to become a reality as soon as possible
typicalguy
not rated yet Feb 12, 2012
This is all over the news. We will know within weeks or a month if it works as I'm sure many desperate patients will get their doctors to prescribe this and those that cant find a doctor will have a reason to take a vacation to mexico. One problem I heard on an interview, the plaques destroy human neurons but not mouse neurons so this is best used on the early stages of the disease to prevent it from developing fully in the first place. It may be able to slow down the progression or even stop it in people with the full blown disease but they will never get those brain cells back.

I wonder if this could be used to treat mad cow and Parkinson's diseases?

Oh and telling someone to "just eat carrots" instead of taking medicine is disgraceful.
Sinister1811
1 / 5 (3) Feb 13, 2012
That's good news for people with Alzheimer's Disease.
TWM
not rated yet Mar 14, 2012
Various natural substances including curcumin have been shown to have a role in preventing/treating Alzheimer's. But I do hate the comments about how evil the Pharmaceutical companies are. I am sure there are many researchers in that industry that are insulted by such comments...I am not in the industry, incidently.

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