Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Drug's effect on Alzheimer's may depend on severity of disease

16.09.2014

A cancer drug that has shown promise against Alzheimer's disease in mice and has begun early clinical trials has yielded perplexing results in a novel mouse model of AD that mimics the genetics and pathology of the human disease more closely than any other animal model.

The drug, bexarotene, was found to reduce levels of the neurotoxic protein amyloid-beta in experimental mice with late-stage Alzheimer's but to increase levels during early stages of disease.

The finding, by researchers at the University of Illinois at Chicago College of Medicine, was reported online in The Journal of Biological Chemistry by Mary Jo LaDu, who in 2012 developed a transgenic mouse that is now regarded as the best animal model of the human disease. That experimental mouse carries a human gene that confers on people a 15-fold elevated risk of developing AD, making it the most important known genetic risk factor for the disease.

Alzheimer's disease is the most common form of dementia, affecting more than five million Americans. The disease is progressive and eventually fatal. One of the hallmarks of AD is the appearance of dense plaques in the brain composed of clumps of amyloid-beta. But recent research indicates that smaller, soluble forms of amyloid-beta -- rather than the solid plaques -- are responsible for the death of nerve cells that leads to cognitive decline.

... more about:
»APOE4 »Alzheimer's »Medicine »UIC

Humans carry a gene for a protein in cells called apolipoprotein E, which helps clear amyloid-beta from the brain by binding to it and breaking it down. LaDu's mice carry the most unfortunate variant in humans, called APOE4, or APOE3, which is neutral for AD risk.

"APOE4 is the greatest genetic risk factor for Alzheimer's disease," said LaDu, who is professor of anatomy and cell biology at UIC. "Our previous work showed that compared to APOE3, the apolipoprotein produced by the APOE4 gene does not bind well to amyloid-beta and so does not clear the neurotoxin from the brain."

Results of previous studies in mice of bexarotene's effect on AD have been mixed, and none of those studies were done in mice that carry a human APOE gene and also develop progressive, AD-like pathology. The UIC research presented in Copenhagen is the first to do so.

LaDu, working with Leon Tai, research assistant professor in anatomy and cell biology; Greg Thatcher, professor of medicinal chemistry and pharmacognosy in the UIC College of Pharmacy; Jia Luo, research assistant professor; and graduate student Sue Lee, gave bexarotene to mice carrying APOE4 or APOE3 for seven days during the early, intermediate, or late stages of AD. The researchers then measured the levels of soluble amyloid-beta in the brains of the mice.

They were able to demonstrate that at the doses given, bioavailability for was not a limiting factor for the activity of the drug, which was able to enter the brain.

In mice carrying human APOE4 with later-stage AD, the researchers saw a 40 percent reduction in soluble amyloid-beta and an increase in the binding of apolipoprotein to amyloid-beta. But in APOE4 or APOE3 mice with earlier-stage AD, the amount of soluble amyloid-beta actually increased. When the researchers gave APOE4 mice bexarotene for one month starting when they had early-stage AD to see if the drug could prevent disease progression, there was no beneficial effect.

Tai thinks that for people who carry the APOE4 gene, short-term treatment with bexarotene in the later stages of disease may be beneficial. But further research is needed, he said, to determine length and timing of treatment -- and, importantly, whether the drug will benefit APOE3 carriers.

"Bexarotene also is extremely toxic to the liver," Tai said. "For prevention, where a drug is given before the symptoms of Alzheimer's disease appear, and likely over longer periods of time, bexarotene is not likely a viable therapeutic because of this known toxicity unless dosing is carefully controlled and patients are closely monitored."

###

Other contributors to the research are Kevin Koster and Nicole Collins, both research associates in the UIC College of Medicine.

The research was supported by an Alzheimer's Drug Discovery Foundation grant P01AG030128 from the National Institute on Aging, and UIC Center for Clinical and Translational Science Grant UL1RR029879.

Sharon Parmet | Eurek Alert!
Further information:
http://www.uic.edu

Further reports about: APOE4 Alzheimer's Medicine UIC

More articles from Life Sciences:

nachricht A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

nachricht On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

A Map of the Cell’s Power Station

18.08.2017 | Life Sciences

Engineering team images tiny quasicrystals as they form

18.08.2017 | Physics and Astronomy

Researchers printed graphene-like materials with inkjet

18.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>