Turning the memory back on through some kind of molecular switch sounds more like a fantasy than a realistic idea. But a group of neuroscientists from the Catholic University and Policlinico Gemelli in Rome has indeed tried to do so in mice by modifying a protein that has key functions in neuronal plasticity. The protein in question is the enzyme LIMK1, which the team of researchers made activatable “on command” through the administration of a molecule called rapamycin. The results of the study were published in Science Advances, and showed great promise in the animal models used.
A molecular switch
The enzyme LIMK1 promotes the formation of so-called dendritic spines, special structures found on the synapses of neurons that in turn enhance the transmission of information within neural networks. “Controlling LIMK1 with a drug – explains Claudio Grassi, director of the Department of Neuroscience at the Catholic University of Rome-means being able to promote the synaptic plasticity and, therefore, the physiological processes that depend on it,” such as precisely those related to memory.
The regulation of LIMK1 was achieved by creating a kind of molecular switch: in essence, the sequence for the expression of a second protein (which will basically be fused to LIMK1) that changes conformation when it binds to rapamycin inserted inside the LIMK1 gene. This conformational change activates LIMK1 and thus promotes the formation of dendritic spines.
Strengthening memory
“In animals with age-related cognitive decline,” explains Cristian Ripoli, professor of physiology at Catholic University, “using this type of gene therapy to modify the LIMK1 protein and activate it with drugs [i.e., rapamycin administration, ed.] resulted in significant improvement in memory. This approach, he continued, theoretically allows manipulation of the neuronal processes that regulate memory under both physiological and pathological conditions.
According to Grassi, the next step will be to test the effectiveness of this type of approach in animal models of neurodegenerative diseases, such as Alzheimer’s disease. “Further studies,” the expert concludes, “will then be needed to validate the use of this technology in humans.
What is rapamycin?
Used in this study as part of a mechanism designed to promote neuronal transmission, rapamycin is an already known molecule that, for the time being, is used in the clinic as an anti-rejection drug after transplants. However, some studies are investigating its effects in the context of aging-related phenomena. In particular, this molecule appears to be able to counteract the reduction in the expression of histones, i.e., the proteins on which DNA is wrapped, that occurs physiologically as age progresses. Past studies have also shown that administering it to “aged” mice for a period of time extends their lives by about 50 percent. Research is still ongoing, including whether the various side effects of rapamycin administration can be remedied.
