A research team led by a BBRF grantee has shown for the first time that the brain contains specialized proteins whose function is to protect synapses from being eliminated. Synapses are the connection points at which the brain’s tens of billions of neurons communicate. The discovery may have valuable implications for development of future treatments for Alzheimer’s disease, as well as schizophrenia and possibly other psychiatric illnesses that involve synapse loss.

At the dawn of life, when the brain of the fetus is beginning to form, an excess of synaptic connections are made. This vigorous process of synapse formation, which is perfectly normal, gives way to an equally normal process of synapse elimination, or “pruning,” which begins in the first years of life and reaches its peak in mid-adolescence.

While synapse creation and synapse elimination are both essential, it is vital that they occur at the proper times and places, in the brain and the rest of the body. During adulthood, the two process balance out. But in certain illnesses, notably Alzheimer’s disease, synapse elimination occurs at an abnormally high rate, a phenomenon associated with memory loss. At the beginning of life, abnormal regulation of synapse formation and pruning has been linked with schizophrenia risk in the child.

Gek-Ming Sia, Ph.D., of the University of Texas Health Science Center in San Antonio, devoted his 2016 BBRF Young Investigator grant to comprehensive study of a protein called SRPX2, which had been linked with increasing the number of synapses formed by neurons in the brain’s cerebral cortex. In a paper recently published in Nature Neuroscience, Dr. Sia and colleagues show that this protein, SRPX2, is present in the brain, and, rather than promoting the formation of new synapses, actually acts to inhibit the mechanism designed to eliminate synapses.

Dr. Sia explains that SRPX2 is part of an immune pathway in the brain called the complement system. “Complement-system proteins are deposited onto synapses,” he says. “They act as signals that invite immune cells called macrophages to come and ‘eat’ excess synapses during development. We have now discovered proteins that inhibit this function and essentially act as ‘don’t eat me’ signals to protect synapses from elimination.”

It is normally the role of SRPX2 and likely other complement inhibitors to prevent runaway activation of the complement system, as may be occurring in Alzheimer’s. Dr. Sia and his team reason that when and where in the brain and body these synapse protectors become active is therefore crucial.

In the paper they just published, the team shows that in the brain, SRPX2 acts to restrict the complement system from eliminating synapses in specific synapse populations and time periods during development. These findings were made in genetically modified mice, in which the specialized functions of SRPX2 and other parts of the mechanism could be isolated and defined.

Knowing that complement-mediated synapse loss occurs in “many neurological diseases,” says Dr. Sia, the challenge for research is to clarify the precise relationship between various inhibitors of the system like SRPX2 and the specific sets of neurons and synapses that they are designed to protect.

It’s possible, his team writes, that “changes in levels of complement inhibitors” could account for different levels of resistance and vulnerability in individuals to various illnesses, from schizophrenia to Alzheimer’s.

In the near term, Dr. Sia’s team will address the specificity issue: whether different neurons produce different complement inhibitors—each, perhaps, protecting a certain subset of synapses. “This could explain why, in certain diseases, there is a preferential loss of certain synapses. It could also explain why some people are more susceptible to synapse loss—because they have lower levels of certain complement inhibitors,” Dr. Sia says.

As this line of research advances, it might eventually test the possibility of using a drug to vary the level of a complement inhibitor such as SRPX2 to protect specific synapses and either lower the risk for an illness or reduce its severity once the disease process has begun.