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As a baby’s brain develops it grows neurons and connections. As the child grows the brain begins a process of paring down some of these connections—also known as synapses.

It has been a mystery how synapses were flagged for removal. Researcher Ben Barres, M.D., Ph.D., professor of neurobiology, feels he has identified the long held mystery.

Barres’ team found that the brain-sculpting process was controlled by a component of the immune system known as the classical complement cascade. The complement cascade is one part of the multipronged attack the immune system launches throughout the body when it detects a foreign invader. It consist of more than 20 small proteins that normally circulate in the blood in their inactive forms, the complement system is triggered into action by an invading parasite. The first activated protein activates a second one, which in turn activates a third, continuing down the line in a domino effect, ultimately yielding a membrane-attack response that kills cells.

The researchers produced the first proof that the complement system also plays a role in the brain by showing that complement proteins bind to unwanted synapses, targeting them for elimination. Future studies will determine how the synapses are marked for death. 

By the age of 10-years-old, synapse elimination normally shuts down. Researchers discovered that this elimination process is reactivated early in glaucoma, a neurodegenerative disease that is a major cause of blindness. They found that the earliest known sign in glaucoma was the complement cascade becoming active at the synapses, followed by a massive synapse loss. Only later did the neurons die, which is the hallmark of neurodegenerative diseases.

What interested the researchers is if the same synapse-elimination process is restarted in other neurodegenerative diseases because these complement proteins are known to be drastically up-regulated in nearly every neurodegenerative disease process that has been examined. Up-regulation is the process by which a cell increases the amount of a molecule, such as a protein, in response to a change in its environment. Alzheimer’s disease, which involves a massive synapse loss, has a hundredfold up-regulation of complement proteins.

Based on the researchers’ finding, that the synapse elimination was reactivated in glaucoma, the researchers’ have a number of collaborations under way to look at the complement cascade’s role in other neurodegenerative disorders, including: Alzheimer’s disease, autism, Lou Gehrig’s disease (ALS), multiple sclerosis, and Parkinson’s disease.

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