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When we think of neurodegenerative disease, we often think of plaques and brain atrophy. For example, it’s long been known that one of the hallmarks symptoms of Alzheimer’s disease is the build-up of amyloid beta, a specialized protein, which then leads to the disorder’s devastating memory problems. But recent work suggests that neurodegeneration likely begins long before such plaques form. And, in fact, new research suggests that neurodegenerative disease, like neurodevelopmental disorders, may actually start with the synapse, the small gap between two neurons in which neurochemical messages are passed.
To prune or not to prune
Synaptic pruning, or the trimming of excess synapses in the brain, is a critical developmental process. One such synapse elimination occurs between early childhood and the onset of puberty, helping the brain strengthen important neural connections and optimize signaling. We still don’t know much about how the brain determines which synapses will be cut during these developmental critical periods, says Beth Stevens, a neurologist at Harvard Medical School and Dana grantee.
“This process is so important to normal brain development. When it goes awry, there are some pretty big consequences. Research has shown that individuals with schizophrenia have fewer dendritic spines; it appears that there’s been too much pruning. And we see the same kind of thing in autism, although at different stages of the developmental process,” she says. “So if we could answer this fundamental question of how these synapses are being tagged for elimination, we may be able to intervene and help.”
But such synaptic deficits are not just limited to development. In her presidential lecture, “Immune Mechanisms of Synapse Loss in Health and Disease,” at Neuroscience 2015 in Chicago, Stevens described how loss of synapses also plays a pivotal role in neurodegeneration as well. Too many snips (or too few, depending) may set the brain up for disease. If we could better understand the upstream regulators of the pruning process, she argues, we would gain critical insight into how and why different synapses are being eliminated, for good or ill.
The complement system and Alzheimer’s
One such upstream regulator may be the complement system, an important part of the immune system that works with antibodies and phagocytic cells (cells that “eat” debris) to help keep the body healthy. The complement system also works in the brain, offering a variety of proteins that help “tag” synapses for elimination during critical periods of development. These proteins, localized to developing synapses during critical periods, somehow tell the brain which synapses go and which synapses stay so the brain “wires up” correctly as it matures.
But Stevens, in her lecture, asked a simple question, “When does neurodevelopmental virtue become neurodegenerative vice?” When might a protein that plays such a pivotal role in normal neurodevelopment wreak havoc on synapses later in life?
Many common neurodegenerative diseases, like Alzheimer’s and Parkinson’s disease, show early synapse loss in important areas of the brain (the hippocampus and the substantia nigra, respectively). Stevens, during her talk, discussed her research on a particular complement protein, C3. She and her colleagues learned that proteins like C3 are upregulated (increase in amount) prior to neuron loss in these disorders. When the group knocked C3 out of mice, they were able to protect aging animals from synapse loss and cognitive decline. This, she argues, shows that the complement system may also play a role in Alzheimer’s disease progression.
The complement system and schizophrenia
Steven McCarroll, a geneticist at Harvard Medical School, says that a single nucleotide polymorphism (SNP) for the C4 gene has long been associated with schizophrenia—but did not correspond with any known disease-associated variant of the gene. “The question, for us, was what this particular SNP might be doing,” he says. “What might it be doing in the central nervous system—and how does that influence the development of this disease?”
Previous research had shown that a different complement protein, C3, promotes pruning during normal brain development. In close collaboration with Stevens’ lab, McCarroll soon learned that C4 marks synapses and debris for removal, driving increased amounts of C3 at synapses to remove that debris during periods of synaptic pruning like adolescence. Both proteins play an important part in the pruning process.
“This is just one story. But it gives us a new biological insight for schizophrenia,” he says. “It also gives us encouragement, even with complex, polygenic illnesses like schizophrenia, that we may be able to come up with some new hypotheses about what’s going on.”
These molecular approaches are exciting—but they can only take us so far, says Paula Pousinha, a researcher at France’s CNRS who studies the roles of different proteins in synapse loss in Alzheimer’s.
“In studies where we focus on what’s happening in the synapse, it’s important for us to go back and try to see how that links back up to behavioral tasks,” she says. “We need a translational approach that comes from the molecules and goes to the behaviors, so we can truly understand the implications and make sure what we are seeing in the synapse corresponds to the disease phenotype.”
Stevens agrees, but is optimistic about how problems at the synapse can help better inform us about the nature of both neurodevelopmental and neurodegenerative disease. “There’s no doubt that we have a lot of work ahead of us. But we now see that these diseases share this common mechanism at the synapse that leads to problems,” she says. “It gives us an opportunity to perhaps intervene, not just the complement system alone, but with other targeted therapies, to slow the progression of these diseases. It offers us a lot of exciting possibilities.”