Immune system destroys Unwanted synapses

TwistedHelix

An interesting new twist: as the brain grows and develops, connections either grow and are reinforced or fade away and die if they are no use. Except that this piece of research shows they don't just wither away or die through Apoptosis, they are actively killed by the immune system . If this process restarts, or never stops, neurodegeneration can result:

[ Back to EurekAlert! ] Public release date: 13-Dec-2007
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Contact: Mitzi Baker
650-723-6912
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 Stevens, 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 Stevens. 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 Stevens. "It was surprising that C1q was the most changed protein; we didn't even think it was expressed in the brain."

Stevens 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, Stevens 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: Stephen Smith, PhD, professor of molecular and cellular physiology; postdoctoral scholar Nicola Allen, PhD; medical student Luis Vazquez, PhD; former postdoctoral scholar Karen Christopherson, PhD; life science technician Navid Nouri; senior research scientist Kristina Micheva, PhD, and postdoctoral scholar Andrew 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 Howard Hughes 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.

PRINT MEDIA CONTACT: Mitzi Baker at (650) 725-2106 (mabaker@stanford.edu)

BROADCAST MEDIA CONTACT: M.A. Malone at (650) 723-6912 (mamalone@stanford.edu)

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_________________
Dom

cheerleader · Posted: Fri Dec 14, 2007 3:20 pm Post subject:

Hi Dom-
Good find!
This is HUGE... Finding the C1q and C3 proteins as the activators of synapse elimination means that drugs which would inhibit these proteins and the cascade process could potentially stop neurodegenerative diseases. for good.

This also provides a comprehensive theory over all auto-immune disease as a protein targeting response to any 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."

Fascinating! Will keep my eye on these Stanford researchers...
AC

gwa · Family Elder Joined: Dec 02, 2005 Posts: 847

Now we have to wait and see what invading parasite is.

gwa

cheerleader · Posted: Fri Dec 14, 2007 7:21 pm Post subject:

Hi GWA,
I don't think we need to wait to find one parasite...I think we've already found many that fit the bill.
I think what this study proves is that there could be any number of parasites, infections, bacteria: whatever crosses the blood brain barrier into the central nervous system- (EBV, Lyme, CpN, heavy metals, you name it) and is recognized as "other" by the immune system.

What matters is that researchers may find that in each case of "CNS invasion" the C1q and C3 proteins are set into action to destroy the invader. These proteins are what begin the cascade of synapse destruction.

I believe that MS is a fingerprint disease. Everyone has a different "invader" that triggers this process. That's why it's so damn hard to find a one size fits all cure. However, if researchers can stop the protein in its tracks, before it begins this attack of the myelin, we can potentially cure autoimmune disease.

(I've often thought that the reason most women have an easier time with MS during pregnancy is because the immune system stops targeting the "other" or "invader" to allow the fetus to survive. Maybe a study of these proteins in pregnant women, to see if they are de-activated during gestation?)

I'm excited by this breakthru.
AC

gwa · Family Elder Joined: Dec 02, 2005 Posts: 847

It sounds good to me too. Hopefully the work will be fruitful soon.

gwa

dignan · Family Elder Joined: Aug 12, 2004 Posts: 1186

Great find Dom. Thank you for posting it. I thought I'd go down the rabbit hole and see what's out there on complement activation and MS. I took as my starting point this statement in the last paragraph of the article you posted:

Lyon · Posted: Sat Dec 15, 2007 12:11 am Post subject:

TwistedHelix · Posted: Sat Dec 15, 2007 8:54 am Post subject:

Thanks for that information , Dignan.
I agree with you, cheerleader, that we have a whole stack of things which have been linked to the beginning of MS, and I think most of us suspected there were multiple "causes". If this research is borne out, it simply won't matter : it's a bit like the coyote in the "Road Runner" cartoons with his detonator and wire leading to dynamite: something presses the handle on the detonator, but it can be anything from a falling rock to a piano – no matter what the trigger is, nothing will happen if the wire is cut.
As Bob pointed out, the placenta skilfully evades the mother's immune system, but it came as a surprise to me to discover that complement is active during normal pregnancy:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1421513
_________________
Dom

Lyon · Posted: Sat Dec 15, 2007 11:39 am Post subject:

Hi Dom,
You've evidently gotten me into the science fiction mode with that Darth Vader comment a while back because an unrelenting phrase that has gone through my mind since, when reading MS research has been "don't forget the faces of your fathers". I don't think that was even from Star Wars, but it was from some space science fiction show I've seen.

It seemingly has nothing to do with MS, but in my whacked out mind it means "never forget the past" which in this case means never forget the early incidence/prevalence/time frame data.

Although I'm convinced there is no such thing as unimportant MS research, there is no doubt that most MS researchers have forgotten the faces of their fathers.

You've mentioned multiple causes for MS and someone else in another post mentioned the same thing in the last day or so. If there is one certainty in MS research it is that MS incidence is owed to an underlying predisposition (not necessarily genetic, despite being commonly accepted) and necessary trigger(s) afterwards.

What that means is that "multiple causes" that we see, or think we see, are nothing more than one of the possible triggers acting after the enabling of the underlying predisposition.

Another confounder of the situation we are dealing with is that, although we know the end of the MS process, we don't know the beginning. When we pop our head into the MS process here and there, we never can be sure if we are viewing an action of the MS process or a reaction to the MS process.

I guess my point is that this finding is interesting and I think will be useful when it's better understood but I'm also sure that it has nothing to do with the predisposition and I'm also convinced that going after the triggers one at a time, whether they be ebv, cpn, amalgam or carbon monoxide, is like the dutch boy trying to plug all the holes in a mile long dike with his fingers. Even in the unlikely event that you were able to plug them all, another would form.

Bob
_________________
Wife diagnosed with MS in Feb. 2006 and is a participant in the Tovaxin IIb clinical trial.

cheerleader · Posted: Sun Dec 16, 2007 2:16 pm Post subject:

Hey Bob-
The placenta uses a "cloaking device!" Now that's pretty sci-fi, you must agree Smile

Thanks for that link. Explains alot. Under the topic of "too much information", I donated my placenta (well actually, it was my son's) to a French scientific research company. Would like to think it went to good use!

Thanks also to Dignan for digging deeper into the proteins and complement cascade. My husband has, along with MS, retinal drusen-a component in macular degeneration. Wonder if we could get him in the compstatin study? Will investigate.

onward,
AC[/i]

TwistedHelix · Posted: Mon Dec 17, 2007 8:13 am Post subject:

Hey Bob,
As usual, we are singing from the same songbook, (except, of course, I'm holding mine the right way up). There must be a predeterminant condition which makes us susceptible to these various triggers otherwise the whole world would end up with MS. However, it may not be a fixable condition: do you remember my analogy a little while ago about the fair haired, fair skinned Scandinavian people? They are "susceptible" or " predisposed" to skin cancer caused by the trigger of sunburn by the very nature of their physical makeup, but it's not exactly a fault, and it can't easily be mended.
It may be a similar case with MS: our predisposition could be something deeply fundamental to our physical being, which causes us to react to the dozens and dozens of potential triggers we may encounter every day. That's why I find the idea of the complement cascade so intriguing: it may represent a bottleneck – somewhere part way between the ever widening range of possible "causes" and the huge array of potential symptoms and chemical imbalances – a narrow point in the pathway to MS which could be closed off. You're right to say that trying to tackle each individual trigger is a losing battle, but maybe the underlying susceptibility is, too, so we need to interrupt the chain a bit further down the line,
_________________
Dom

Lyon · Posted: Mon Dec 17, 2007 2:28 pm Post subject:

You let me off easy on that one Dom, thanks! Considering I'm the guy who says that the only thing certain about MS is that it sucks, I shouldn't have used the word "certain" (regarding predisposition and trigger(s)), but I was just to tired and lazy last night to edit it into "almost certain".
Bob
_________________
Wife diagnosed with MS in Feb. 2006 and is a participant in the Tovaxin IIb clinical trial.

OddDuck · Posted: Mon Dec 17, 2007 4:23 pm Post subject:

Hi, there! I haven't posted here in ages, but I still lurk now and again. This thread on complement and C1q caught my eye. I did some research into this myself back in 2004. See the thread:

http://www.thisisms.com/ftopict-433-c1q.html

The whole research I did begins with PTX3 and how it pertains to MS (as causal. How coincidental.) Then you'll see halfway down the page how PTX3 triggers C1q. A quick excerpt - from halfway down the thread:

"Pentraxin 3 (PTX3) is a recently characterized member of the pentraxin family of acute-phase proteins produced during inflammation. Classical short pentraxins, C-reactive protein, and serum amyloid P component can bind to C1q and thereby activate the classical complement pathway. Since PTX3 can also bind C1q, the present study was designed to define the interaction between PTX3 and C1q and to examine the functional consequences of this interaction."

I speculated and wondered back then what PTX3 (and therefore C1q) was doing in MS.

I hope everyone is doing well and Happy Holidays all!

Deb

Sharon · Posted: Mon Dec 17, 2007 5:57 pm Post subject:

Deb -

Welcome back! Hope you are well, and Merry Christmas to you also.

Sharon