In 2015, the team of Hélène Marie, research director at the IPMC in Sophia Antipolis, made a major discovery as part of an international collaboration. A discovery which would undo many beliefs surrounding Alzheimer’s disease, starting with the certainty that everything depends on the famous Amyloid Beta, this peptide which accumulates to form senile plaques. In an article then published in the journal Nature, the Sophia Antipolis researchers revealed the existence of another key peptide, called AETA, and showed that direct contact with small quantities of this soluble peptide immediately reduced the activity of neurons in the central nervous system. Beyond providing proof that Alzheimer’s disease is much more complex than previously assumed, this work opened the way to other therapeutic avenues. But, with a prerequisite: removing the mystery of AETA’s “mode of operation”. And this is the new feat accomplished by the Sophian team, published in the journal Neuron.
“Since its description in 2015, we have been trying to understand how this peptide affects brain activity”, introduces Hélène Marie. First important discovery: “It modifies in a very particular way a receptor called NMDA, very involved in 99% of our cognitive functions” ; it is in fact via this receptor – which passes ions through the membrane of neurons – that the neurotransmitters attach and transmit information to the brain. “We discovered that by binding to NMDA receptors, AETA inhibits their ion channel function and increases another of their atypical functions: the weakening of synapses, a crucial process for regulating connectivity between neurons, allowing the transmission of information and storage, particularly of memories.”
The peptide discovered by the Azuréens would thus act as a key unlocking this atypical function. Then using complex chemogenetic techniques (2)researchers will show that AETA production is increased when neurons are activated in vivo, providing evidence that AETA-dependent regulation of NMDA receptor activity is an essential physiological mechanism for information processing cerebral.
A role in brain pathology
Under physiological conditions, AETA therefore plays a subtle regulatory role. But could it contribute to certain diseases? “We already know that the receptor that it regulates is at the heart of numerous neurodegenerative pathologies: Alzheimer’s, Parkinson’s, Huntington’s, certain epilepsies… but also psychiatric ones, such as depression or schizophrenia. We can therefore wonder about potential links between the levels of this peptide, its activity, and the occurrence of these diseases.”
Strong argument in favor of this hypothesis, particularly concerning Alzheimer’s disease: “Elevated levels of AETA were detected in sick patients. At the same time, a weakening of synapses in the brain was demonstrated, correlating with memory loss.”
We can therefore see part of the chronicle emerging: excess AETA, via its action on NMDA receptors, weakens synapses, inducing a loss of connections between nerve cells, and therefore a decline in cognitive functions. On the other hand, when this peptide is at insufficient levels, “There could be hyperactivation of the ‘channel function’ of NMDA receptors, and therefore of neuronal networks, with here also a disruption of cognitive functions.”
The next step in these major discoveries? Trying to find innovative molecules capable of interfering with AETA, and restoring “normal” brain activity in pathological situations. Major research in which several scientists around the world are involved, around Hélène Marie’s team.
1. Areas located between two neurons and ensuring the transmission of information from one to the other.
2. Genetic tool activated by a chemical compound to control the activity of neurons.
