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Blocking Fibrin Signaling in the Brain Improves MS and AD Models

Robinson, Richard

doi: 10.1097/01.NT.0000550496.78144.15
At the Bench
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ARTICLE IN BRIEF

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Researchers found that the neuroinflammatory signaling of fibrin can be blocked while normal clotting function is maintained, using an antibody that targets a single epitope of the clotted protein. Treatment of mice with the antibody improved cellular and some clinical signs in animal models of Alzheimer's disease and multiple sclerosis, suggesting it may provide a safe way to reduce neuroinflammation and slow disease progression.

Compromise of the blood-brain barrier is a characteristic of multiple neurologic diseases, including Alzheimer's disease (AD) and multiple sclerosis (MS). A leaky barrier allows fibrinogen into the brain and triggers formation of a fibrin clot, which in turn, sets off an inflammatory cascade.

This fibrin-induced neuroinflammation contributes to pathogenesis of both AD and MS, but targeting it by blocking fibrinogen has been too risky for clinical development because of concerns for disruption of hemostasis. Now, in a new study in the November issue of Nature Immunology, researchers show that the neuroinflammatory signaling of fibrin can be blocked while normal clotting function is maintained, using an antibody that targets a single epitope of the clotted protein. Treatment of mice with the antibody improves cellular and some clinical signs in models of both AD and MS, suggesting it may provide a safe way to reduce neuroinflammation and slow disease progression.

“They have hit a very important pathophysiological strike point to make a potential difference in neuroinflammation,” said Lawrence Steinman, MD, FAAN, professor of pediatrics, neurology and neurological sciences at Stanford University, who was not involved in the study. “The challenge will be to ensure it is safe.”

“For several decades, neuropathologists have used fibrinogen as a marker for blood-brain barrier disruption,” explained the principal investigator of the new study, Katerina Akassoglou, PhD, senior investigator at the Gladstone Institute of Neurological Disease and professor of neurology at the University of California, San Francisco. “When there is a disruption of the barrier, it allows large molecules from the blood, such as fibrinogen, to enter the brain.”

More recent research, from Dr. Akassoglou's lab and others, has shown that the fibrin clot triggers a neuroinflammatory cascade, and that depletion of fibrinogen, either genetically or with anticoagulants, reduces neuroinflammation and provides protection in models of both MS and AD. Further work demonstrated that one of the main drivers of the pathogenic effect was activation of microglia.

“Fibrinogen is not only a hemostatic factor,” Dr. Akassoglou explained. “When converted to fibrin, it exposes a new domain,” a so-called cryptic epitope 18 amino acids long, which in the periphery binds to and activates complement receptor on macrophages, and in the brain binds to and activates the same receptor on microglia.

That led Dr. Akassoglou to ask how this activation might best be prevented. Targeting the receptor itself was likely to cause problems, she said. “The complement receptor is very pleiotropic — it has many other functions, including developmental and immunomodulatory functions such as synaptic pruning. So for selectivity for disease, I reasoned it would be better to go after its pathogenic ligand, which is not present in the normal brain,” namely that cryptic epitope on fibrin, which only becomes exposed as a result of clotting.

Earlier work from her lab had shown that the domain could be genetically ablated to suppress neuroinflammation without compromising hemostasis, indicating it was not involved in the clotting process itself. “That was an indication that it could be targeted separately,” Dr. Akassoglou said. “The fact that we would be targeting a cryptic epitope, and that we already had genetic validation that this would not interfere with normal clotting in the mouse, gave us some hope that we might be able to block it.”

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STUDY DETAILS

To do so, Dr. Akassoglou developed a monoclonal antibody, dubbed 5B8, against the epitope. She showed that the antibody bound to fibrin, but not fibrinogen, and that when it did so it blocked microglial activation in vitro without affecting hemostasis. Fibrin increased activity of NADPH oxidase, a promoter of oxidative stress that is elevated in both MS and AD; antibody treatment reduced that activity.

In mice with experimental autoimmune encephalitis, a model for MS, treatment with 5B8 delayed onset and reduced neurologic signs when given prophylactically; when given after disease onset, treatment reduced relapses, and only 25 percent of the mice developed paralysis versus more than 75 percent of mice receiving a control antibody. Treatment reduced microglial activation and damage to spinal cord axons.

The 5XFAD double transgenic mouse is a model for severe AD in which fibrin can be detected in the brain within three months of birth. Treatment with 5B8 beginning at 3.5 months reduced the loss of cholinergic neurons and reduced the concentration of activated microglia around amyloid-beta plaques, but it did not reduce the number of plaques themselves. Dr. Akassoglou has not yet tested the effects of treatment on cognition but noted this is a key question for future research.

“More work will be needed to better characterize this antibody,” Dr. Akassoglou cautioned, “but the ability to target innate immunity in either MS or AD could represent an important therapeutic strategy,” she said. “Innate immunity has many protective functions, so a challenge in the field has been that a global shutdown of the innate immune response is unlikely to be clinically viable. But we think there might be room for ligand-selective targeting as an alternative. This approach could be especially valuable for neutralizing the toxic effects of the blood in the brain in neurological diseases with vascular abnormalities and blood-brain barrier leakage.”

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The ideal timing and duration of therapy are still unclear, she added. But she pointed out that the normal mechanisms for removal of fibrin, and therefore reduction of the pathogenic signaling, are impaired in many neurologic diseases, and so may result in a chronic inflammatory response even after the blood-brain barrier has been repaired.

“Neuropathology suggests that clotted fibrin may remain in the brain for a long time,” she said, which may require prolonged treatment to continue blockade of the inflammatory signal.

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EXPERT COMMENTARY

“This research is a step in the right direction to understand the constellation of contributors to neuroinflammation in both multiple sclerosis and Alzheimer's disease,” commented Costantino Iadecola, MD, professor of neurology and director of the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine in New York. “Fibrin is not the sole contributor, of course, but it may be a really important contributor, and that would make it worth targeting. Dr. Akassoglou has been a pioneer in pushing this idea forward.”

“However,” he noted, “this strategy absolutely has the same challenges as other antibody-based therapies and is likely to be only one aspect of a multi-pronged approach to slow neurodegeneration.”

Finally, he cautioned, the degree of benefit that could be expected from even an effective anti-fibrin strategy may be patient-specific, since the mix of pathogenic factors may differ from patient to patient.

Dr. Steinman, of Stanford, commented, “This work is exquisitely detailed, and I think it has big implications, but the challenge is targeting fibrin safely. It is a pathway that is underexplored for very good reasons — as soon as you start modulating clotting, you have the potential for unwanted bleeding or coagulation. The antibody may be dramatically useful, but someone will have to work up the courage to try it. I think bringing this approach forward is possible, but those are the issues that will have to be overcome.”

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DISCLOSURES

Dr. Akassoglou is co-founder of MedaRed, Inc. and has received royalty payments for patents. Drs. Iadecola and Steinman had no disclosures.

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LINK UP FOR MORE INFORMATION:

•. Ryu JK, Rafalski VA, Meyer-Franke A, et al Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration https://www.nature.com/articles/s41590-018-0232-x. Nat Immunol 2018;19(11):1212–1223.
    © 2018 American Academy of Neurology