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Type of sugar may treat atherosclerosis, mouse study shows

Type of sugar may treat atherosclerosis, mouse study shows

Researchers have long sought ways to harness the body’s immune system to treat disease, especially cancer. Now, scientists have found that the immune system may be triggered to treat atherosclerosis and possibly other metabolic conditions, including fatty liver disease and type 2 diabetes.

Studying mice, researchers at Washington University School of Medicine in St. Louis have shown that a natural sugar called trehalose revs up the immune system’s cellular housekeeping abilities. These souped-up housecleaners then are able to reduce atherosclerotic plaque that has built up inside arteries. Such plaques are a hallmark of cardiovascular disease and lead to an increased risk of heart attack.

“We are interested in enhancing the ability of these immune cells, called macrophages, to degrade cellular garbage — making them super-macrophages,” said senior author Babak Razani, MD, PhD, an assistant professor of medicine.

Macrophages are immune cells responsible for cleaning up many types of cellular waste, including misshapen proteins, excess fat droplets and dysfunctional organelles — specialized structures within cells.

“In atherosclerosis, macrophages try to fix damage to the artery by cleaning up the area, but they get overwhelmed by the inflammatory nature of the plaques,” Razani explained. “Their housekeeping process gets gummed up. So their friends rush in to try to clean up the bigger mess and also become part of the problem. A soup starts building up — dying cells, more lipids. The plaque grows and grows.”

In the study, Razani and his colleagues showed that mice prone to atherosclerosis had reduced plaque in their arteries after being injected with trehalose. The sizes of the plaques measured in the aortic root were variable, but on average, the plaques measured 0.35 square millimeters in control mice compared with 0.25 square millimeters in the mice receiving trehalose, which translated into a roughly 30 percent decrease in plaque size. The difference was statistically significant, according to the study.

The effect disappeared when the mice were given trehalose orally or when they were injected with other types of sugar, even those with similar structures.

Found in plants and insects, trehalose is a natural sugar that consists of two glucose molecules bound together. It is approved by the Food and Drug Administration for human consumption and often is used as an ingredient in pharmaceuticals. Past work by many research groups has shown trehalose triggers an important cellular process called autophagy, or self-eating. But just how it boosts autophagy has been unknown.

In this study, Razani and his colleagues show that trehalose operates by activating a molecule called TFEB. Activated TFEB goes into the nucleus of macrophages and binds to DNA. That binding turns on specific genes, setting off a chain of events that results in the assembly of additional housekeeping machinery — more of the organelles that function as garbage collectors and incinerators.

“Trehalose is not just enhancing the housekeeping machinery that’s already there,” Razani said. “It’s triggering the cell to make new machinery. This results in more autophagy — the cell starts a degradation fest. Is this the only way that trehalose works to enhance autophagy by macrophages? We can’t say that for sure — we’re still testing that. But is it a predominant process? Yes.”

The researchers are continuing to study trehalose as a potential therapy for atherosclerosis, especially since it is not only safe for human consumption but is also a mild sweetener. One obstacle the scientists would like to overcome, however, is the need for injections. Trehalose likely loses its effectiveness when taken orally because of an enzyme in the digestive tract that breaks trehalose into its constituent glucose molecules. Razani said the research team is looking for ways to block that enzyme so that trehalose retains its structure, and presumably its function, when taken by mouth.

This article was published in Science Daily dated ‘Jun. 07, 2017’

Protein in Parkinson’s provokes the immune system

Protein in Parkinson’s provokes the immune system

Bits of a protein that builds up in Parkinson’s disease trigger the immune system, causing it to tag them as foreign invaders.

In a blood test, immune cells called T cells became activated when exposed to the protein in about 40 percent of Parkinson’s patients in a new study. This autoimmune response may contribute to the progression of the disease, the researchers report online June 21 in Nature.

Neurodegenerative disorders like Parkinson’s “have not really been thought of as autoimmune disorders,” says co-author David Sulzer, a neuroscientist at Columbia University and the New York State Psychiatric Institute in New York City. “The data strongly indicate that we better look at autoimmune responses as at least one of the links in the chain of developing Parkinson’s.”

Patients with Parkinson’s experience tremors and slowed movement, among other symptoms. Scientists don’t know exactly what causes Parkinson’s, but during the disease, many nerve cells located in a region of the brain called the substantia nigra die. These neurons release dopamine, a chemical messenger that is sent to other parts of the brain to coordinate movement. Little blobs known as Lewy bodies, primarily made of a protein called alpha-synuclein, also build up in these neurons.

One of the immune system’s jobs is to distinguish between the body’s own components and foreign substances, such as bacteria and viruses. Certain types of immune cells capture proteins and present them to T cells, which figure out, “Is itself? Or is it nonself? Does it come from bacteria, a virus or some kind of invader?” Sulzer says. In autoimmune disorders, the immune system makes an error in judgment.

Sulzer and colleagues had previously discovered that the substantia nigra neurons that release dopamine can present proteins to T cells, if given a signal from the immune system. If the body cannot degrade alpha-synuclein properly, bits of these proteins that build up in the nerve cells could end up being presented to T cells, which might see them “as not being self, even if it comes from you,” Sulzer says. In the new study, the researchers tested for an immune response to two different, small stretches of the alpha-synuclein protein using blood samples from 67 people with Parkinson’s and 36 healthy people.

Indeed, the two pieces of alpha-synuclein were essentially recognized as foreign by T cells in Parkinson’s patients, Sulzer says. He speculates that the autoimmune response contributes to the progression of the disease, rather than the start, as it’s triggered by the inability to properly break down alpha-synuclein.

“As with any good study, there are more questions than answers,” says neuroscientist Andrew West of the University of Alabama at Birmingham. Assuming the work can be replicated in other Parkinson’s patients, “the question becomes: When do these changes in immune cell activation become apparent? Early in the disease, or later?” he says.

This article was published in Science News dated ‘Jun. 21, 2017’