14 December 2007

Immune System Sculpts The Brain

by Kate Melville

The synapse elimination that occurs during the normal development of a child's brain seems to be directed by the immune system, say researchers at the Stanford University School of Medicine.

Beyond understanding how connections are weeded out in a normal, developing brain, the finding could also help explain some neurodegenerative disorders - such as glaucoma, Alzheimer's disease and multiple sclerosis - that result from the loss of too many synapses.

Synapse elimination occurs during the normal development of a child's brain, but until now, no one knew how certain synapses were flagged for removal. "We have identified the long-mysterious mechanism by which excess synapses are sculpted away in the developing brain," said the study's senior author, Ben Barres, in the journal Cell.

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. Consisting 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.

Barres' team 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.

When children reach the age of 10, synapse elimination normally shuts down. But the researchers found that this elimination process becomes reactivated very 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 synapses, followed by massive synapse loss. Only much later did the neurons die, which is the hallmark of neurodegenerative diseases.

"This is interesting, as these complement proteins are known to be drastically up-regulated in nearly every neurodegenerative disease process that has been examined," said Barres. 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 massive synapse loss, has a hundredfold up-regulation of complement proteins.

Based on their finding that synapse elimination was reactivated in glaucoma, the research team have a number of collaborations under way looking at the complement cascade's role in other neurodegenerative disorders, including Alzheimer's, autism, Lou Gehrig's disease (known as ALS), multiple sclerosis and Parkinson's.

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Source: Stanford University Medical Center