Israeli scientists from the Technion – Israel Institute of Technology have developed an artificial molecule that could inhibit the development of Alzheimer’s disease, conceivably paving the way for better treatment of the disease.
The Technion scientists collaborated with The French National Centre for Scientific Research (CRNS) and published their findings in the weekly peer-reviewed Angewandte Chemie scientific journal published on behalf of the German Chemical Society.
The study was led by Professor Galia Maayan and doctoral student Anastasia Behar from the Schulich Faculty of Chemistry at the Technion, in collaboration with Prof. Christelle Hureau from the Laboratoire de Chimie de Coordination du CNRS, Toulouse, France.
The findings showed that an accumulation of copper ions, when interacting with the amyloid beta (Aβ) can lead to cell toxicity, causing dangerous conditions, including degenerative diseases of the brain, like Alzheimer’s. This accumulation of copper disrupts the removal of the Aβ , a peptide linked to the plaques that form in the brains of Alzheimer’s patients.
A 2013 study appearing in the Proceedings of the National Academy of Sciences journal written by a group led by Rashid Deane, a research professor in the University of Rochester’s Medical Center department of neurosurgery, said that copper accumulation in the body increases the progression of Alzheimer’s disease by preventing toxic proteins from leaving the brain. More specifically, copper ion interaction with the Aβ promotes ROS, or reactive oxygen species, highly reactive chemicals formed from oxygen. The production of ROS due to metal ions, like copper, leads to oxidative damages to the Aβ peptide and the potential formation of amyloid plaque.
Researchers have learned that the breakdown of the copper- Aβ complex and the removal of copper from the amyloid, prevents cells’ death and inhibition of the disease. The extraction of copper is done by a process called chelation or using molecules that bind the copper ions and extract them from the amyloid.
Developing the foundation
Technion Chemistry Professor Galia Maayan did not begin her career by studying copper ion accumulation and its impact on degenerative diseases. Instead, she simply focused on the molecule.
“I’m a chemist. So I look at a molecule and I said, ‘Oh I have this molecule, I have this metal ion, in this case, copper, how can I design something that is selective for copper?’ And then I will think about other applications,” she tells NoCamels, “When I did my postdoc at NYU, I learned a lot about these peptide mimics or peptoids. I developed chelators that are not selective [to specific metal ions.]”
Prof. Maayan developed the foundation for copper and zinc-binding of peptoids and investigated how peptoids bound them — something she says no one had ever done up to that point — but it wasn’t until she met her first PhD student, Maria Baskin, (another author of the paper), that she understood that the molecules could be good for chelating metal ions related to specific diseases.
“We discussed copper, and then we started to think about Alzheimer’s,” she says, “and then we started to work on it.”
Prof. Maayan and Baskin developed the first generation of chelator molecules selective to copper. But they were not water soluble, she explains. “In order to start making the drugs you want to develop, you need your molecule to be, at least to a certain extent, water soluble.”
The Technion researchers developed their own method of making the molecule water soluble, without changing its shape or organization and patented the result. Thus, a water soluble peptoid chelator was created that could still selectively bind copper. Meanwhile, Anastasia Behar, who joined Prof. Maayan’s lab while completing her Master’s in Chemistry at the Technion, was sent to France for three months to work with CRNS after Prof. Maayan made a connection with Prof. Christelle Hureau.
Behar tells NoCamels that in France, the researchers created targeted environments where they could simulate processes in the brain where the accumulation of metals bound to Aβ was happening.
“Then we added our molecule and tested if it can interact with the amyloid-beta, take out the copper, and stop the radical production, which the molecule did eventually,” she explains.
“While working on the molecule, Nastia [Anastasia] learned how to do biochemical experiments to show the biology that the molecule can do. All of the things that we think can lead us toward future development of peptoids as drugs for Alzheimer’s,” Prof. Maayan said.
The Technion researchers developed their own method of making the molecule water soluble, without changing its scaffold or the way it was organized. This was tested in France. The water soluble peptoid chelator, a synthetic molecule dubbed P3, was able to perform its task selectively. It strongly binds copper and forms CuP3, extracting the copper from the amyloid. By doing this, it inhibits and even suppresses the formation of harmful oxidizing agents, without creating new processes, which neutralize amyloid toxicity.
Prof. Maayan says it’s important to note that the molecule that the researchers established is not the actual molecule they would like to be used when creating drug treatments for Alzheimer’s.
“It has solubility issues, stability issues. This is not a molecule we’re going to develop. This is just a base,” she tells NoCamels, “We are going to take it further and develop more and more molecules that will be better. Right now we’ve just put down the foundation and this is the breakthrough. We will make molecules that are more feasible later on.”
The next step, Prof. Maayan explains, is to go beyond the mimicking of an environment of a cell or of the brain in terms of a PH solution and to do more in-vitro experiments, or experiments with cells.
“We’ll do some in vitro experiments, then we will optimize the chemistry again, and then go back to in vitro until we are ready to go in vivo [with a living organism.],” she says, “It’s a long process. It can take several years, but we see the way so it’s not vague. We see the way and we now know what we need to do.”
