Impaired Immune Cells May Contribute to Parkinson’s Progression, Study Suggests

monocytes Parkinson's

Reduced viability and impaired activity of monocytes — a subset of immune cells that circulate in the blood — may contribute to the progression of Parkinson’s disease.

That discovery, by researchers from Aarhus University in Denmark, may further understanding of the underlying mechanisms involved in the development and progression of this complex disease.

“The research project confirms a growing theory that Parkinson’s disease is not only a brain disease, but is also connected with the immune system. Both in the brain and the rest of the body,” Marina Romero-Ramos, PhD, associate professor at Aarhus University and senior author of the study, said in a press release.

The study, “Alterations in Blood Monocyte Functions in Parkinson’s Disease,” was published in the journal Movement Disorders.

Parkinson’s disease is characterized by the accumulation of misfolded alpha-synuclein protein in the brain. This protein is toxic for brain cells, causing them to die and resulting in the characteristic motor symptoms associated with the disease.

However, the underlying mechanism that triggers this disease is not restricted to accumulation of alpha-synuclein. Indeed, growing evidence suggests that abnormal forms of the protein may originate in the gut, which then migrate to brain where it becomes toxic to brain cells.

These recent findings suggest that the immune system also may play a central role in this process, as circulating immune cells should be the first front to fight and destroy these potentially harmful abnormal proteins.

Researchers set up a new study to explore the role of circulating immune cells, in particular monocytes, in the development and progression of Parkinson’s disease.

Monocytes are a type of white blood cells that secrete several signaling molecules that are increased in Parkinson’s patients, and also are important mediators of the inflammatory response associated with diseases such as multiple sclerosis and stroke.

Researchers analyzed blood samples from 29 Parkinson’s patients and 20 age- and sex-matched volunteers without any sign of neurodegenerative disease.

Although at the time of sample collection no significant differences were observed between patients and controls, after culturing blood samples for two hours the team found that the count of viable cells was decreased significantly in female Parkinson’s patients compared to controls, with males showing a similar trend.

This reduction in viability also was observed in the number of monocytes, which were significantly lower in female patients than healthy female controls (5,780 vs. 12,813). This tendency also was observed in male patients (14,479 vs. 19,447).

In addition to the low viability of the cells, the team also found that monocytes of Parkinson’s patients were less responsive to stimuli. The cells showed less signs of activation when exposed to a pro-inflammatory chemical and to alpha-synuclein clumps.

“The lack of a response to stimulation suggests that the [Parkinson’s disease] patient cells are unresponsive and maybe even overstimulated, thus unable to respond to further stimulation,”  the researchers wrote.

Further experiments revealed that monocytes from healthy volunteers secreted the signaling molecule IL-10 when in the presence of alpha-synuclein fibrils, while monocytes from Parkinson’s patients did not. This difference suggested that patients’ monocytes were unable to respond to alpha-synuclein stimulation, suggesting a differential activation and functional status of these cells.

“This knowledge may in the long term lead to the development of supplementary immune-regulating treatment being combined with the current medical treatment with the drug L-dopa, which only has an effect on the brain and the symptoms,” said Sara Konstantin Nissen, PhD, lead author of the study. “We believe such an additional drug might help to slow down the progression of the disease.”

These findings provide further support to the idea that Parkinson’s disease is more “than just a brain disorder,” which “requires a change of views among medical doctors and neurologists,” she said.

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Long-Lived Gut Macrophages Key for Survival of Nerve Cells, Could Help Parkinson’s Research


Long-lived macrophages in the mouse gut are crucial for the survival of nerve cells in the gastrointestinal tract and for proper digestion, a finding that sheds new light not only on neurodegenerative conditions of the intestine, but also of the brain, researchers believe.

The study, “Self-Maintaining Gut Macrophages Are Essential for Intestinal Homeostasis,” was published in the journal Cell.

Macrophages are immune cells involved in the detection and destruction of bacteria and other harmful organisms, and they also participate in the initiation of inflammatory responses. This type of white blood cell also is a source of growth factors and support to different tissues, helping them function and develop properly. As such, macrophages play two opposing roles, of soldier and nourisher, at the same time.

Their correct functioning in the gut is critical, as these cells have to be able to differentiate between harmful bacteria, harmless bacteria and nutritional components. So-called gut-resident macrophages (gMacs) also contribute to the release of the anti-inflammatory molecule interleukin-10. They can be subdivided into various subpopulations with distinct characteristics.

Researchers believed that, after birth, intestinal macrophages were short-lived (approximately three weeks) and continuously replaced by bone marrow-derived monocytes (the largest of all white blood cells),  which then would transform into macrophages.

Now, KU Leuven researchers have found this theory is not entirely correct. “We’ve discovered that a small part of the macrophages in mice is long-lived. We marked certain macrophages and found that they still functioned after at least eight months,” Guy Boeckxstaens, MD, PhD, the study’s senior author, said in a press release.

Specifically, researchers found that during embryonic life gMacs (self-maintaining macrophages) with a distinct pattern of gene expression colonize specific spots in the intestine, such as blood vessels and the myenteric plexus — the major source of nerve supply to the gut, connected to muscle cells. Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein

After birth, these spots receive monocyte-derived gMacs, which implies that, similar to the heart and the lungs, the adult gut contains both embryonic, or long-lived, and monocyte-derived macrophages.

The scientists also found that long-lived macrophages support the organization and permeability of the gut’s lamina propria – a type of connective tissue – and muscularis externa, a muscle layer closely interacting with the intrinsic nervous system of the gastrointestinal tract, called enteric nervous system. Deleting the gMac population led to loss of enteric neurons, blood vessel leakage, and reduced intestinal motility.

“If the long-lived macrophages don’t do their job properly, already after a few days the mice suffer from digestive problems. This leads to constipation or even the complete degeneration of the nervous system in the stomach and intestine,” said Sebastiaan De Schepper, the study’s first author.

Overall, researchers believe that besides helping to better understand the diversity of this cell population, the results also “demonstrate the strategic role of self-maintaining [long-lived] macrophages in gut homeostasis and intestinal physiology.”

Investigators are now planning to study the role of these cells in disorders affecting nerve cells of the intestine, such as in obesity and diabetes.

“Moreover, the results can also be meaningful for brain research. In the brain, we have microglia, similar long-lived macrophages that play an important role in neurological conditions such as Alzheimer’s and Parkinson’s disease. Scientists currently believe that nerve cells in these patients die off because microglia do not provide sufficient care. Maybe one day research of the intestine can offer us a better understanding of these brain conditions,” Boeckxstaens said.

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Source: Parkinson's News Today