Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists discover that three molecules may be developed into new Alzheimer’s drugs

25.07.2005


A team of scientists has discovered three molecules –– from a search of 58,000 compounds –– that appear to inhibit a key perpetrator of Alzheimer’s disease.

Each of the three molecules protects the protein called "tau," which becomes hopelessly tangled in the brains of patients with Alzheimer’s. The finding is promising news for the development of drugs for the disease.

Ken Kosik, co-director of the Neuroscience Research Institute at the University of California, Santa Barbara, headed the effort to find these molecules. The results of the study are published in the July issue of the journal Chemistry and Biology, released on Friday, July 22.



As baby boomers grow older, the incidence of Alzheimer’s, already increasing, will rise much more. "Our approaches to the disease are flagrantly inadequate," said Kosik. "There are a couple of FDA-approved drugs that help a little, but don’t modify the disease. They give a little bit of symptomatic relief, but don’t change the inexorable progression of the disease."

He said that new insights made over the past decade help to understand the molecular and genetic basis of the disease and these can now be built upon for the development of treatments. "There is no doubt that we need new approaches," said Kosik. "The insights gained about the mechanisms of the molecular and genetic basis of the disease are beginning to add up and can be harnessed for treatments."

Alzheimer’s involves a complicated, interwoven series of regulatory steps of genes and proteins "talking" to each other, he explained. "When the conversation goes awry the disease process begins. And it is not just one gene or one protein causing the damage."

The complexity of Alzheimer’s means that several different medications will likely be needed to control it, said Kosik. The same is true for many other diseases –– from AIDS to cancer. "It is likely that we will need to strategically target different aspects of the disease and put them together."

Kosik and his team chose to focus on the neurofibrillary tangles of neurons in the brain that, along with senile plaques, characterize Alzheimer’s disease. The tangles are made of "tau," a protein that is also present normally in the brain.

"Tau goes wrong and becomes pathological when it becomes intensely phosphorylated," said Kosik. "This means that many phosphate groups attach to tau--modify it--and cause it to become dysfunctional."

The culprit is an enzyme, called CDK5, that attaches the phosphate to the tau protein, facilitating the disease process. The researchers set out to find a way to inhibit this enzyme, to keep it from putting any phosphate on tau.

In the laboratory, they purified the enzyme and purified tau protein, and watched tau get phosphorylated by the enzyme. They then performed a library search of small molecules (58,000 of them) in an attempt to find those that would prevent phosphorylation. Small molecules are preferred because they are more easily used as a drug since they can get through the body and into cells. It is also important to find molecules that will cross the blood brain barrier.

They then set up a test of nearly 400 small molecules that fit their criteria. The test results showed three small molecules that can inhibit the enzyme. These are candidates for development as drugs.

Kosik explained that proteins are strings of amino acids folded into small globs. All proteins that happen to be an enzyme involved in phosphorylation have one thing in common. They have a pocket that is almost always in the same place and this is where the phosphate attaches to the enzyme, in this case CDK5. To get a molecule that specifically prevents the enzyme from binding at the pocket is difficult.

Of the three compounds that the research group found, the scientists were able to locate where they bind. They found that one binds in the pocket, another binds at the edge of the pocket, and a third appears to bind completely outside the pocket. The scientists are most interested in the second and third compounds.

"This is the first demonstration that we can find small molecules that can more specifically affect the phosphorylation of tau by CDK5," said Kosik.

In terms of future directions, Kosik said, "There is lots to do here, lab testing, testing in animals, etc. But we have made an important step forward toward developing treatments for this disease."

He noted that this work is of a type usually performed by pharmaceutical companies, but in this case was completed in an academic environment.

Gail Gallessich | EurekAlert!
Further information:
http://www.ucsb.edu

More articles from Life Sciences:

nachricht Single-stranded DNA and RNA origami go live
15.12.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard

nachricht New antbird species discovered in Peru by LSU ornithologists
15.12.2017 | Louisiana State University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: First-of-its-kind chemical oscillator offers new level of molecular control

DNA molecules that follow specific instructions could offer more precise molecular control of synthetic chemical systems, a discovery that opens the door for engineers to create molecular machines with new and complex behaviors.

Researchers have created chemical amplifiers and a chemical oscillator using a systematic method that has the potential to embed sophisticated circuit...

Im Focus: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

Engineers program tiny robots to move, think like insects

15.12.2017 | Power and Electrical Engineering

One in 5 materials chemistry papers may be wrong, study suggests

15.12.2017 | Materials Sciences

New antbird species discovered in Peru by LSU ornithologists

15.12.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>