Alzheimer’s disease: protein switches receptor ion channel

The brain consists of millions of neurons that communicate with each other and process information. So-called NMDA receptors play a significant role in the majority of cognitive processes of the central nervous system. For most neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, scientists have identified changes in the function of NMDA receptors. Studies have shown that these receptors can work in two different ways: They can function as an ion channel, but can also operate via an atypical mode, which is associated with a conformational change.

Researchers at LMU’s Biomedical Center (BMC) and the German Center for Neurodegenerative Diseases (DZNE), led by Dr. Michael Willem, have now demonstrated in a collaboration with French scientists that the protein AETA, which they had already described in an earlier study, plays an important role in the regulation of NMDA receptors.

In the earlier study, the researchers showed that AETA inhibits neural activity. Now the team has conducted a new study to investigate how this happens and reveal the underlying mechanism. As the researchers demonstrate, AETA acts on an important neural NMDA receptor called NMDAR. This receptor plays a major role in learning processes, for example, and is activated by the release of the neurotransmitter glutamate – but only when another molecule binds to NMDAR as a co-agonist. As the scientists show, AETA displaces the co-agonist from the ion channel and directly regulates its activity in this manner. This prevents the opening of the ion channel. However, processes that are based on a mode of action of NMDAR produced by conformational modifications remain possible. Consequently, AETA seems to be directly involved in processes of neural plasticity and learning. With their results, the researchers have thus deciphered a previously unknown role for the protein. “Whether conclusions can be drawn for the role of AETA in neurological diseases associated with the NMDAR ion channel will be for future research to ascertain,” say the authors.

Jade Dunot, Sebastien Moreno, Carine Gandin, Paula A. Pousinha, Mascia Amici, Julien Dupuis, Margarita Anisimova, Alex Winschel, Magalie Uriot, Samuel J. Petshow, Maria Mensch, Ingrid Bethus, Camilla Giudici, Heike Hampel, Benedikt Wefers, Wolfgang Wurst, Ronald Naumann, Michael C. Ashby, Bodo Laube, Karen Zito, Jack R. Mellor, Laurent Groc, Michael Willem und Hélène Marie: APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors. Neuron, 2024