Cancer drugs and Alzheimer's, Oh my

[bobze]

Alerted to this from a friend who is an alumni of Case

Drug Quickly Reverses Alzheimer's Symptoms in Mice
Case Western Reserve Researchers Discover FDA-approved Drug Rapidly Clears Amyloid from the Brain and Reverses Cognitive Defects

CLEVELAND – Feb. 9, 2012 – 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. Food and Drug Administration 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 amyloid beta proteins. 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 memory deficits 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 brain function, are tremendously exciting and suggest great promise in the utility of this approach in treatment of Alzheimer's disease."

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.
The Science study was co-authored by John R. Cirrito, Jessica L. Restivo, Whitney D. Goebel, Washington University School of Medicine; C.Y. Daniel Lee, Colleen Karlo, Adriana E. Zinn, Brad T. Casali, Case Western Reserve University School of Medicine; Donald A. Wilson, New York University School of Medicine, and Michael J. James, Kurt R. Brunden, Perelman School of Medicine, University of Pennsylvania.

Very excited to read the article in Science, when it comes out--Granted this is of course a press-release and prone to a certain kind of hype. That said still looks promising, I'm not aware of any potential treatments yet that have had such a profound effect on mouse models. Of course this is in mouse models and possibly won't translate well into humans--Though that this is an on the market FDA approved drug, I think provides some hope for good translation.

Edit: The article is available online already;
http://www.sciencemag.org/content/early/2012/02/08/science.1217697

Will give a read tomorrow with my thoughts after this terrible [strike]hell[/strike] exam week is over!

 

[Ygggdrasil]

The article was published today online on the Science website:

Cramer et al. 2012. ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models. Science. http://www.sciencemag.org/content/early/2012/02/08/science.1217697.abstract

This research is definitely promising, and because bexarotene is already a drug approved for other uses, clinical testing of the drug should go quickly.

There is, however, reason to believe that this will not be a magic bullet for Alzheimer's. As the article mentions, mutations to ApoE are major risk factors for Alzheimer's. If many patients with Alzheimer's have non-functional forms of ApoE, it is unclear whether boosting the expression ApoE using bexarotene will facilitate clearance of the amyloid plaques in these individuals. After all, if the protein is not working correctly, having more of it around may not fully correct the underlying defect with the protein.

Furthermore, it's important to remember that mouse models of diseases are not perfect. Cramer et al. use APP/PS2 mice which carry mutations in the amyloid beta precursor protein and presenilin 2, causing the mice to develop the amyloid beta plaques that many believe are responsible for Alzheimer's disease. However, research also suggests that dysfunction of another protein tau may also be an important driver of Alzheimer's disease. Unfortunately, the APP/PS2 mice used in this study do not recapitulate the tauopathies seen in human Alzheimer's cases, so it is unclear whether the drug can correct problems associated with dysfunctional tau as well. Furthermore, although the APP/PS2 mice suffer cognitive decline, neurons in the mouse model do not die off as they do in human Alzheimer's, which could explain why the researchers could so easily reverse the cognitive and memory defects.

Nevertheless, this study provides a very promising lead for a potential therapy for Alzheimer's disease.

[edit: Here's a nice article from Scientific American which talks about the study as well as some of the criticisms I mentioned above:
http://www.scientificamerican.com/article.cfm?id=alzheimers-disease-sympto ]

 

[Ryan_m_b]

Granted this is of course a press-release and prone to a certain kind of hype.

I'm short on time so haven't read the paper yet but this comment I definitely agree with. The news last night (C4) opened with "scientists in America have Alzhiemer's breakthrough!" they went on for ages before they even bothered to mention it was in a mouse. Then they interviews people with Alzhiemer's and talked about how their lives are etc which I can't condone at all. All they've done is get people's hopes up for something which only has potential at the moment (how many times have we cured various diseases in mice only for it to not work in humans?)

Will give a read tomorrow with my thoughts after this terrible [strike]hell[/strike] exam week is over!

Best of luck bobze

 

[Ygggdrasil]

A year ago we were wondering whether the results of this study would hold up in humans. Apparently, the results don't even seem to hold up in mice!

Bexarotene, a cancer drug touted as a potential treatment for Alzheimer’s disease, may not be the blockbuster remedy scientists were hoping for, according to several analyses published in Science on 24 May. Four independent research groups report that they failed to fully replicate striking results published in the journal last year by Gary Landreth, a neuroscientist at Case Western Reserve University School of Medicine in Cleveland, Ohio, and his colleagues.

http://www.nature.com/news/studies-cast-doubt-on-cancer-drug-as-alzheimer-s-treatment-1.13058

For the actual papers see https://www.sciencemag.org/content/340/6135.toc#TechnicalComments

 

[LudusRex]

I am also very excited about this breakthrough in Alzheimer's research. The use of an already FDA-approved drug to potentially treat this devastating disease is a promising approach. However, as with any new treatment, further studies and clinical trials will be necessary to determine its effectiveness and safety in humans. It is also important to note that Alzheimer's disease is a complex condition and may require a combination of therapies to effectively treat it. Nonetheless, this discovery opens up new avenues for research and brings hope to the millions of people affected by Alzheimer's. I look forward to reading the full article in Science and following the progress of this potential treatment.