Immune System may target some brain synapses

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Public release date: 13-Dec-2007

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Contact: Mitzi Baker

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Stanford University Medical Center

Immune system may target some brain synapses, Stanford researchers find

STANFORD, Calif. - A baby's brain has a lot of work to do, growing more

neurons and connections. Later, a growing child's brain begins to pare

down these connections until it develops into the streamlined brain of

an adult.

Now researchers at the Stanford University School of Medicine have

discovered the sculptor behind that paring process: the immune system.

The value of this discovery goes 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 neuronal connections, which are known as synapses.

The advance, which has implications for drugs that could halt or reverse

such conditions, will be published in the Dec. 14 issue of the journal Cell.

It was widely known that synapse elimination occurs during 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, MD,

PhD, professor of neurobiology.

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, he said.

First author Beth s, PhD, a postdoctoral scholar in Barres' lab,

said these findings in glaucoma made the team wonder if the same

synapse-elimination process is restarted in other neurodegenerative

diseases. " It's an exciting thought, as this would be the earliest sign

of disease so far, " she said.

The Barres laboratory has long been interested in the development and

function of glial cells, which constitute around 90 percent of the cells

in the human brain. These cells - specifically oligodendrocytes and

astrocytes - provide support and protection for neurons, but the main

role of the glia is a mystery, said Barres. His lab has been

systematically identifying proteins and chemical factors that glial

cells produce to modulate the activity of neurons.

The current finding of the complement cascade's involvement in the

synapse-paring process was a bit of serendipity, said s. The team

knew the process coincided with the appearance of astrocytes in the

developing brain, so they decided to run a microarray - the lab tools

that can screen thousands of genes at a time - to see which neuronal

genes were most active when neurons are exposed to astrocytes.

Unexpectedly, they found that the first protein in the complement

cascade, called C1q, was the most up-regulated of all proteins.

" The role of the complement system was known in the rest of the body,

but this opened up the question of what was going on in the brain, " said

s. " It was surprising that C1q was the most changed protein; we

didn't even think it was expressed in the brain. "

s went on to painstakingly characterize the role of the complement

cascade. She ultimately showed that astrocytes make complement proteins

that " tag " brain synapses during development. Complement protein C1q,

and another one called C3, were required for synapse elimination.

Based on their finding that synapse elimination was reactivated in

glaucoma, s and Barres 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.

" As synapse loss and C1q up-regulation are prominent features of all

these diseases, our findings imply that drugs that blockade the

complement cascade may provide a new treatment for many different

neurodegenerative diseases, " Barres said.

###

Other Stanford researchers who contributed to this study are:

, PhD, professor of molecular and cellular physiology; postdoctoral

scholar Nicola , PhD; medical student Vazquez, PhD; former

postdoctoral scholar son, PhD; life science technician

Navid Nouri; senior research scientist a Micheva, PhD, and

postdoctoral scholar Huberman, PhD.

This work was supported by grants from the National Institute on Drug

Abuse, a Larry H. Hillblom Fellowship, a Human Frontier Fellowship, a

Helen Hay Whitney Fellowship and the Medical Institute.

Stanford University Medical Center integrates research, medical

education and patient care at its three institutions - Stanford

University School of Medicine, Stanford Hospital & Clinics and Lucile

Packard Children's Hospital at Stanford. For more information, please

visit the Web site of the medical center's Office of Communication &

Public Affairs at http://mednews.stanford.edu.

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