Anle138b, a new small-molecule drug, can restore brain function and memory in a mouse model of Alzheimer’s disease, an international team of researchers has shown. Scientists foresee that the drug could be used to treat Alzheimer’s and other neurodegenerative diseases such as Parkinson’s and ALS.

The experimental drug works by stopping toxic ion flow in the brain that is known to trigger nerve cell death.

“This is the first drug molecule that can regulate memory loss by directly blocking ions from leaking through nerve cell membranes,"

said co-senior author Ratnesh Lal, a professor of bioengineering at the University of California San Diego.

Anle138b, Amyloid-beta And Tau

Various studies have shown associations with Alzheimer’s disease and 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 change 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 brain function, 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.

Human Research Needed

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.

A new Alzheimer’s mouse model that more closely mimics the human disease, recently reported from Perelman School of Medicine researchers, may help.

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.

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.

Funding came from the German Center for Neurodegenerative Diseases (DNZE) , Max Planck Society, the Hans and Ilse Breuer Foundation, University of Malta, Deutsche Forschungsgemeinschaft, the EU, and National Institute on Aging of National Institutes of Health.

Ana Martinez Hernandez, Hendrik Urbanke, View ORCID ProfileAlan L Gillman, Joon Lee, Sergey Ryazanov, Hope Y Agbemenyah, Eva Benito, Gaurav Jain, Lalit Kaurani, Gayane Grigorian, Andrei Leonov, Nasrollah Rezaei‐Ghaleh, Petra Wilken, Fernando Teran Arce, Jens Wagner, Martin Fuhrman, Mario Caruana, Angelique Camilleri, Neville Vassallo, Markus Zweckstetter, Roland Benz, Armin Giese, Anja Schneider, Martin Korte, Ratnesh Lal, Christian Griesinger, Gregor Eichele, Andre Fischer The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology EMBO Molecular Medicine (2017) e201707825

Image: Retrovirus labeled granule neurons in the dentate gyrus of Alzheimer disease mouse model. Credit: Ávila, J., CC BY-SA 2.5

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