Experimental drug blocks toxic ion flow linked to Alzheimer's disease

December 5, 2017
PET scan of a human brain with Alzheimer's disease. Credit: public domain

An international team of researchers has shown that a new small-molecule drug can restore brain function and memory in a mouse model of Alzheimer's disease. The drug works by stopping toxic ion flow in the brain that is known to trigger nerve cell death. Scientists envision that this drug could be used to treat Alzheimer's and other neurodegenerative diseases such as Parkinson's and ALS.

"This is the first molecule that can regulate memory loss by directly blocking ions from leaking through nerve cell membranes," said Ratnesh Lal, a professor of bioengineering at the University of California San Diego and co-senior author of the study.

Various studies have linked Alzheimer's to the accumulation of two particular proteins in the brain called amyloid-beta and tau. One theory is that these protein clusters create pores in nerve cell membranes that allow ions to travel in and out uncontrollably. This would alter ion levels inside the cells and in turn trigger neuronal dysfunction and cell death.

The new drug, a small molecule called anle138b, blocks these pores from moving ions in and out of nerve cells. Anle138b attaches to both amyloid-beta and tau protein clusters and deactivates the pores created by these clusters.

Researchers administered anle138b to mice with a genetic predisposition for developing an Alzheimer's-like condition. The mice had symptoms such as abnormal , impaired memory and high levels of either amyloid-beta or tau proteins in the brain. Treatment with anle138b normalized brain activity and improved learning ability in mice.

The study was led by the German Center for Neurodegenerative Diseases, the University Medical Center Göttingen, the Braunschweig University of Technology, the Max Planck Institute for Biophysical Chemistry, the Center for Nanoscale Microscopy and Molecular Physiology of the Brain in Göttingen, Germany, and the University of California San Diego. Researchers published their findings on Dec. 5 in EMBO Molecular Medicine.

Christian Griesinger, a professor at the Max Planck Institute for Biophysical Chemistry and co-senior author of the study, noted, "The drug is able to reach the brain when taken orally. Therefore, it is easy to administer, and we are currently performing toxicology studies to eventually be able to apply anle138b to humans."

The team cautions that since the drug has so far only been tested in mice, it is unclear how well it would perform in humans. "I would like to emphasize that none of the current animal models fully recapitulate the symptoms seen in Alzheimer's patients. Thus, care has to be taken when interpreting such data. However, our study offers evidence that anle138b has potential for neuroprotection," said André Fischer, a senior researcher at the German Center for Neurodegenerative Diseases and the University Medical Center Göttingen, who is also a co-senior author of the study.

While collaborators in Germany will be pursuing clinical studies in human patients with , Lal and his research group at the UC San Diego Jacobs School of Engineering are particularly interested in testing anle138b on a variety of other diseases that are linked to toxic ion flow caused by amyloid proteins, including diabetes, tuberculosis and certain types of cancer. Lal's group has performed extensive research on amyloid ion channels and their roles in these diseases. "Blocking the ion leakiness of amyloid channels using anle138b could be an effective therapy for various diseases," Lal said.

Lal serves as co-director for the Center of Excellence for Nanomedicine and Engineering, a subcenter of the Institute of Engineering in Medicine at UC San Diego. His research group will also work on targeted delivery of the drug using their patent pending "nanobowls," which are magnetically guided nanoparticles that can be packed with drugs and diagnostic molecules, deliver them to particular sites in the body and release them on demand. Future studies will focus on using these nanobowls to deliver anle138b to the , as well as other diseased tissues and organs affected by toxic amyloid-beta ion channels.

Explore further: New drug candidate ameliorates Alzheimer's and other brain diseases

More information: "The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology." EMBO Molecular Medicine (2017). DOI: 10.15252/emmm.201707825

Related Stories

New drug candidate ameliorates Alzheimer's and other brain diseases

October 13, 2015
Professor Armin Giese from the Center for Neuropathology and Prion Research at the LMU Munich and researchers at the Max Planck Institute for Biophysical Chemistry in Göttingen and at the German Center for Neurodegenerative ...

Alzheimer's disease might be a 'whole body' problem

October 31, 2017
Alzheimer's disease, the leading cause of dementia, has long been assumed to originate in the brain. But research from the University of British Columbia and Chinese scientists indicates that it could be triggered by breakdowns ...

BACE-Inhibitor successfully tested in Alzheimer's animal model

July 28, 2017
The protein amyloid beta is believed to be the major cause of Alzheimer's disease. Substances that reduce the production of amyloid beta, such as BACE inhibitors, are therefore promising candidates for new drug treatments. ...

'Pac-Man' gene implicated in Alzheimer's disease

July 26, 2016
A gene that protects the brain from the harmful build-up of amyloid-beta, one of the causative proteins implicated in Alzheimer's disease, has been identified as a new target for therapy by NeuRA researchers.

Recommended for you

Gene mutation causes low sensitivity to pain

December 13, 2017
A UCL-led research team has identified a rare mutation that causes one family to have unusually low sensitivity to pain.

Activating MSc glutamatergic neurons found to cause mice to eat less

December 13, 2017
(Medical Xpress)—A trio of researchers working at the State University of New York has found that artificially stimulating neurons that exist in the medial septal complex in mouse brains caused test mice to eat less. In ...

Scientists discover blood sample detection method for multiple sclerosis

December 13, 2017
A method for quickly detecting signs of multiple sclerosis has been developed by a University of Huddersfield research team.

LLNL-developed microelectrodes enable automated sorting of neural signals

December 13, 2017
Thin-film microelectrode arrays produced at Lawrence Livermore National Laboratory (LLNL) have enabled development of an automated system to sort brain activity by individual neurons, a technology that could open the door ...

Intermittent fasting found to increase cognitive functions in mice

December 12, 2017
(Medical Xpress)—The Daily Mail spoke with the leader of a team of researchers with the National Institute on Aging in the U.S. and reports that they have found that putting mice on a diet consisting of eating nothing every ...

Discovery deepens understanding of brain's sensory circuitry

December 12, 2017
Because they provide an exemplary physiological model of how the mammalian brain receives sensory information, neural structures called "mouse whisker barrels" have been the subject of study by neuroscientists around the ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.