ARTICLE IN BRIEF
Treatment with amyloid beta inhibited production of a range of pro-inflammatory cytokines, and led to a reduction in proliferation of CD4+ T-effector cells in an animal model of multiple sclerosis.
DR. LAWRENCE STEINMA...Image Tools
Is the villain of Alzheimer's disease really a misunderstood hero in the body's response to inflammation? That's the potential conclusion of a provocative study showing that peripheral administration of amyloid beta (Abeta) reverses paralysis and reduces inflammation in two different animal models of multiple sclerosis (MS). This surprising result, reported in the Aug. 1 Science Translational Medicine, prompted investigators to suggest that the role of amyloid be reconsidered in other neurologic diseases.
“Over many years, we and others have noticed that amyloid precursor protein and Abeta,” its amyloid cleavage product, “are present in MS brain lesions and the spinal fluid of MS patients,” said Lawrence Steinman, MD, professor of neurology and neurological sciences at Stanford University. “So the question was, ‘What role is it potentially playing in MS?’”
DR. TIMOTHY VOLLMER:...Image Tools
To find out, Dr. Steinman and his team began with a simple experiment, a peritoneal injection of Abeta peptides 40 and 42 — the two main cleavage products of the precursor — into mice with experimental autoimmune encephalitis (EAE), the standard, albeit imperfect, model of MS. “My expectations were that the highest probability was that nothing would happen, and the second highest probability was that it might make the disease worse and we would make a few interesting observations.”
Instead, the mice got better. “I thought to myself, ‘It must be a mistake. Let's do it again.’” But each time the results were the same. Injected before the onset of symptoms, treatment delayed the symptoms and reduced their incidence and severity. Injection after symptom onset led to a reversal of disease progression within several days of treatment, an effect that lasted over the subsequent weeks of the experiment. The beneficial effect of amyloid administration was seen in EAE induced with either TH1 or TH17 cells, two pro-inflammatory helper cells that are used to study different inflammatory pathways in MS.
Treatment with Abeta inhibited production of a range of pro-inflammatory cytokines, and led to a reduction in proliferation of CD4+ T-effector cells, which, Dr. Steinman said, play a central role in EAE pathogenesis. The immunosuppressive effect was not due to simple cytotoxicity, and furthermore could be transferred to treatment-naïve mice by transferring TH17 cells collected from the spleen and lymph nodes of treated mice.
“This key experiment,” Dr. Steinman said, “indicates that the immunosuppressive effect of Abeta 42 on immune cells residing outside the brain is sufficient to ameliorate EAE,” meaning that the therapeutic treatment effect occurs peripherally, not centrally. There were no signs that administration of Abeta led to accumulation of amyloid in the brain.
Finally, the researchers induced EAE in mice lacking amyloid precursor protein. Without the ability to make Abeta, their disease was worse, Dr. Steinman said, strengthening the case that Abeta acts to damp down the immune response.
“But the story is much richer than that,” Dr. Steinman said. Unpublished work in his lab has since shown that other amyloid proteins have the same protective effect, including ones implicated in other neurologic diseases, such as tau and huntingtin. “There's a long list of amyloid proteins, and they're all immunosuppressive.”
The picture that Dr. Steinman said is emerging from this work is that amyloid may be involved with tissue repair. Among the top molecules found in MS brain lesions are a long list of amyloid proteins, including alpha B-crystallin, the chief component of the eye's lens, and amyloid beta. Many of the same molecules form in response to physical stress, such as blows to the head.
“If I am a famous boxer, and I get punched in the head repeatedly, one of the responses to that stress is to make alpha B-crystallin, and also to make amyloid beta. In MS, it doesn't look like it's causing dementia, Dr. Steinman said, citing a 2001 report in Science. [See references.] “It may be a molecule that's involved in an orchestrated response of our tissues to heal themselves.” One study, he noted, has found an inverse correlation in MS patients between cleaved amyloid precursor protein in the cerebrospinal fluid and disability.
“So it certainly changes the way we ought to think about these proteins. Does it mean the dominant hypothesis in Alzheimer's disease is wrong? No, I'm not saying that at all. I'm still teaching the residents and medical students the standard hypothesis, but like all attractive hypotheses, when there is an anomaly, the anomaly may be highly instructive. We'll just have to see.”
When asked if MS therapies based on Abeta are likely, Dr. Steinman said, “Not any time soon” — but mainly because Abeta itself is likely to be seen as too much of a neurologic villain to entertain its development as a treatment for a brain disorder. Instead, he said, it may be fruitful to pursue one of the other amyloid proteins that are presumed to be less toxic. Also, noting the plethora of treatments for relapsing-remitting MS, he suggested that progressive disease might be the most obvious arena for development of therapy. Indeed, he noted, mice with a progressive form of EAE seemed to respond most strongly to treatment with amyloid beta.
In an editorial accompanying the research report, Reinhard Hohlfeld, MD, and Hartmut Wekerle, MD, noted that the precise mechanism of the beneficial effects of Abeta treatment remains to be worked out, but that modulation of autoreactive T cells appears to be at the heart of it. However, they wrote: “The use of Abeta as a potential therapy for MS will require careful and extensive testing before it can be applied to patients.” Dr. Hohlfeld is professor at the Institute for Clinical Neuroimmunology at Ludwig Maximilians University in Munich, Germany, and Dr. Wekerle is director and scientific member at the Max Planck Institute of Neurobiology in Martinsried, Germany.
The risk, they suggested, is that peripherally administered Abeta could lead to a significant increase in the concentration of the circulating protein, well above normal levels. “If peripherally injected Abeta peptides reach the brain, they could act as seeds triggering the formation of amyloid deposits, eventually promoting or even initiating Alzheimer's-like disease.”
Nonetheless, they said, “As is not uncommon in science, an initially paradoxical observation may offer fresh insights about disease pathogenesis and stimulate new ideas about therapeutic interventions.” Understanding amyloid's role in altering MS pathogenesis is also likely to go a long way to unraveling its precise role in the degenerative process of Alzheimer's disease.
Timothy Vollmer, MD, professor and director of clinical research in the neurology department at the University of Colorado School of Medicine in Aurora, who was not involved with the study, commented: “This is really a novel bit of science. The challenge for us is to figure out how Abeta has this effect.” Most interesting, he said, would be to understand what role Abeta may be playing in the natural history of MS. “We are still struggling to understand why an acute relapse actually ends. We don't really understand the biological basis of that, and this paper for the first time offers a possible mechanism,” based on the damping down of pro-inflammatory processes.
While there are many MS therapies available and in development, there may be room for another, based on its regulatory, rather than immunosuppressive, properties. “This biology could fit very nicely into a combination therapy,” he said.
• Grant JL, Ghosn EE, Steinman L, et al. Reversal of paralysis and reduced inflammation from peripheral administration of β-Amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis. Sci Transl Med
• Hohlfeld R, Wekerle H. β-Amyloid: Enemy or remedy? Sci Transl Med 2012;4(145):145fs24.
• Mai W, Hu X, Wang Y, et al. Cerebrospinal fluid levels of soluble amyloid precursor protein and β-amyloid 42 in patients with multiple sclerosis, neuromyelitis optica and clinically isolated syndrome. J Int Med Res
• Chabas D, Baranzini SE, Steinman L, et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science