Tiny components of amyloid plaques, the notorious protein clumps found littering the brains of people with Alzheimer’s disease, might fight inflammation. Researchers report that several of these sticky protein fragments, or peptides, glom onto inflammatory compounds and reverse paralysis in mice that have a condition similar to multiple sclerosis. A fragment of tau protein, which shows up in other brain deposits in Alzheimer’s patients, has a similar effect.
When tested on blood taken from three MS patients, the tau peptide weeded out some inflammatory culprits there, too, researchers report in the April 3 Science Translational Medicine.
“This is a seriously good study. It opens up more questions than it answers,” says Jian-Guo Geng, a cell biologist at the University of Michigan in Ann Arbor who wasn’t part of the research team. “But I don’t think we’re anywhere close to using these peptides for treatments.”
Amyloid is a broad term for clusters of protein in the brain, including those arising with the aid of misfolded versions of tau or another protein implicated in brain disease called a prion. Viewing amyloid-forming peptides as good guys runs against the scientific thinking, since amyloid plaques are a hallmark of Alzheimer’s disease. But study coauthor Lawrence Steinman, a neurologist at Stanford University, points out that the actual role of amyloid plaques in the disease is unclear. He suggests the tiny peptides holding the plaques together might have an alternative, useful role in the body.
Last year, Steinman and his team showed that injecting mice with amyloid improves symptoms in animals with the MS-like condition (SN: 9/22/2012, p. 14). Separately, Geng reported in 2012 that mice genetically engineered to make extra amyloid could fend off the MS-like disease, and that knocking out the amyloid-making capacity worsened symptoms in animals.
The new study goes a step further toward working out how amyloid fights disease in mice. In MS, inflammation is the enemy, damaging the fatty coatings on nerve sheaths in the central nervous system. A breakdown of that nerve insulation results in disordered nerve signaling and symptoms that can include weakness, loss of motor control, vision problems, loss of sensation and other problems.
Steinman and his colleagues identified several peptides, each only six amino acids in length, that seem to knock down inflammation when they twist to form sticky structures called fibrils. Steinman likens the peptide fibrils to sponges, because of their ability to bind to and contain compounds that trigger inflammation.
The researchers injected various peptides that can form amyloid in mice that had become disabled by the MS-like condition. Several of the peptides – including fragments of heat shock proteins, tau protein and prion protein – reversed the animals’ paralysis during treatment. The effect later faded.
Blood samples from treated mice showed that heat shock and tau peptide fibrils had reduced levels of several proteins that cause inflammation, including interleukins 2 and 6. Compared with animals that received no fibril treatment, the animals’ brain tissue had less inflammation.
When the scientists cultured human blood from MS patients with the tau fibril, the sticky peptide bound to dozens of compounds, including many molecules involved with inflammation.
The misfolded versions of tau, prions and amyloid protein can all form deposits in the brain, and it is the stickiness of fibrils that enables sheets of proteins to aggregate into these deposits, Steinman says. Those deposits have earned fibrils a nasty reputation.
“We have to keep an open mind,” he says. “Most molecules are nuanced in function. In certain circumstances, they can cause harm or benefit.”