A paper came out this week from the Stanford lab of Ben Barres, M.D., Ph.D. It’s titled "A Dramatic Increase of C1q Protein in the CNS during Normal Aging,
” and is a wonderful example of how conventional thinking has no monopoly on being right. It also makes a good case for the nervous system playing good cop/bad cop at the same time: we may protect and serve you but we can turn vicious on you too.
The gist of the paper is this: nerves degenerate, especially as they age. This is the result of synapses – the tree-branch like interconnections between nerve cells – being tagged and eliminated by the immune system, which is supposed to protect them. While the paper specifically discusses the role of immune proteins in the onset of cognitive loss and Alzheimer’s disease, the implications for intervening in the process of synapse loss are much broader, including many conditions from glaucoma to Parkinson’s and even spinal cord injury (see below).
Barres, who is a member of the Reeve International Research Consortium on Spinal Cord Injury reported six years ago in Cell
that a microglial protein called C1q initiates what is called a complement cascade – this is an immune response by a small army of 20 immune proteins that in normal circumstances clean up cellular debris. "We always think of them [microglia] as the garbage collecting cells in the brain," Barres told a reporter.
These cells are a lot more than nervous system janitors. In 2012, in Neuron
, Barres, in collaboration with Beth Stevens, Ph.D., formerly a colleague at Stanford, now at Harvard, showed that it is the brain’s own immune cells, indeed the microglia, that attack and devour synapses tagged by the complement system.
“In neurodegenerative disease, synapses start to massively degenerate,” Barres said. “We think the complement cascade kills them.”
The function of C1q is essential to normal nervous system development. They help prune, or sculpt excess synapse formation as the nervous system wires itself up the first time. What has been discovered, though, is that C1q shows up, rather substantially, in the central nervous system of older animals. The new paper notes that elevated C1q is concentrated at synapses. This makes synapses more vulnerable to significant destruction by bad cop immune cells, triggered perhaps by a secondary event.
"No other protein has ever been shown to increase nearly so profoundly with normal brain aging," said Barres. Age-related mouse and human brain tissue showed as much as a 300-fold buildup of C1q. "The 300-fold rise in C1q levels we saw in 2-year-old mice – equivalent to 70- or 80-year-old humans – knocked my socks off," Barres said. "I was not expecting that at all."
C1q accumulation is a fact, but in itself is not necessarily a direct factor in synapse degeneration. But as the C1q cells accumulate they may ignite a serious complement onslaught if something activates toxic partner cells, the astrocytes. This could be triggered by trauma, by inflammation related to infection, or even by tiny, sub-clinical strokes. Most cells in the body are able to mount a natural defense against a complement-cascade attack; nerve cells don’t have such a shield. So, when astrocytes get activated, their recruitment of C1q and the other cells of the complement group may set off a frenzy of synapse destruction that spreads "like a fire burning through the brain," Barres said.
The new paper no doubt has the Alzheimer’s community abuzz, as it more or less pivots the opposite direction from the prevailing theory that has underpinned years of research and billions in failed clinical trials -- the notion that the disease is caused by amyloid plaques which cause inflammation and synapse loss. “We think people have the ordering backwards,” Barres said. “We believe the complement turns on first and starts to kill synapses. If that’s true, the implication is we just need to block this complement cascade to treat Alzheimer’s.”
From a Stanford press release:
"Our findings may well explain the long-mysterious vulnerability specifically of the aging brain to neurodegenerative disease," he said. "Kids don't get Alzheimer's or Parkinson's. Profound activation of the complement cascade, associated with massive synapse loss, is the cardinal feature of Alzheimer's disease and many other neurodegenerative disorders. People have thought this was because synapse loss triggers inflammation. But our findings here suggest that activation of the complement cascade is driving synapse loss, not the other way around."
Barres is working on ways to interrupt the activation of astrocytes. From the paper:
“...our findings have important implications for understanding and treating cognitive decline in the aging CNS and for understanding neurodegenerative diseases, such as Alzheimer’s disease. Will drugs that prevent an increase in C1q, or that block its function, lessen cognitive decline, and/or restore cognitive function in normal aging?
Barres is already on the case for making such a drug. He and biotech scientist/entrepreneur Armon Rosenthal formed a company two years ago, Annexon. One thing they are after is a molecule that binds and thus inhibits the C1q protein. While Alzheimer’s is obviously a pressing medical and social issue, and a condition with a lot of market upside, a drug to block the complement cascade could be useful for any number of neurodegenerative diseases. “If we can block this pathway, we should be able to block the neurodegeneration process in many, many people.” It’s a “no-brainer,” said Barres, that blocking the complement cascade will block, and perhaps even restore, neurodegeneration.
Annexon is discovering and developing novel disease modifying drugs for neurodegenerative disorders that represent unmet medical needs. We are building an antibody platform that targets various components of the complement system. Our most advanced programs target orphan auto-immune neurological disorders from which we will expand in to Alzheimer's disease, glaucoma, traumatic brain injury, spinal cord injury, and multiple sclerosis.
More on the SCI angle
The role of the complement cascade has been the focus of the Aileen Anderson
lab at the University of California, Irvine, for more than a decade. Anderson, now a member of the Reeve Consortium, is perhaps better known for her work with stem cells and the science behind the current StemCells, Inc. clinical trial in Switzerland. But it was her work with transgenic mice in studying immune response that attracted the stem cell company to her research in the first place.
In 2004 Anderson was first author with principal investigator Carl Cotman at UCI (who at the time was a Consortium member) of a paper, “Activation of complement pathways after contusion-induced spinal cord injury.
From that paper:
Complement protein immunoreactivity was predominantly found in cell types vulnerable to degeneration, neurons and oligodendrocytes, and was not generally observed in inflammatory or astroglial cells. Surprisingly, immunoreactivity for complement proteins was also evident 6 weeks after injury, and complement activation was observed as far as 20 mm rostral to the site of injury. Axonal staining by C1q and Factor B was also observed, suggesting a potential role for the complement cascade in demyelination or axonal degeneration. These data support the hypothesis that complement activation plays a role in SCI.
Anderson’s group continues to study the complement system. A primary focus of her lab is on learning about the cellular source of complement in the spinal cord, and using transgenic mice lacking complement components to clarify the role of complement to CNS injury.
It appears that blocking C1q after SCI might be a good thing. A 2008 paper from Anderson showed that initiation of the classical complement pathway via C1q is detrimental to recovery after SCI: “Deficiency in complement C1q improves histological and functional locomotor outcome after spinal cord injury