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A new study,
done with mice and published in the Federation of the American
Societies of Experimental Biology Journal, suggests that
miscommunication between the immune system and brain may be to blame
for extended sickness symptoms and other cognitive disorders in
elderly people and animals with an infection. "In the course of
our other studies on inflammation and aging, we repeatedly saw that
old animals suffered an exaggerated inflammatory response in the
brain compared to younger adults when their peripheral immune system
was experimentally activated," said Rodney W. Johnson, a professor
of integrative immunology and behavior in the Department of Animal
Sciences. "Knowing the role of brain inflammation in behavioral
deficits and neurodegenerative diseases, we felt this could be
important, especially because immunity is often suppressed in the
elderly, making them more susceptible to infections.
Johnson and his colleagues compared behavior in young adult and
aged mice that were made temporarily ill by exposure to
lipopolysaccharide, or LPS, a molecule present on E. coli and other
gram-negative bacteria that strongly activates the immune system.
"When a person or pet develops an infection, their behavior
changes: They stop eating; they become lethargic; they have reduced
cognitive abilities," Johnson said.
How do you know a mouse feels sick? Like unhealthy humans, mice
show decreased appetite, weight loss and less social interaction,
said Johnson, who likened his own lack of interest in getting up off
the couch to greet visitors when he is sick to a mouse's lack of
curiosity about new cage mates when it is sick.
LPS injections caused older mice to stop eating for a longer
amount of time, lose more weight and show less social behavior than
younger mice.
"As expected, young adults showed signs of improvement eight
hours after LPS treatment and fully recovered by the next day, but
the aged animals still were 50 to 60 percent depressed," Johnson
said. "We've completed follow-up studies that show aged animals are
still depressed three to four days later."
Johnson and colleagues also studied how aging affects the
response of microglial cells -- key immune cells in the brain --
during a peripheral infection.
It is important that the peripheral immune system inform the
brain of an infection, Johnson said. "The peripheral immune system
signals microglia to secrete inflammatory cytokines that cause
behavioral changes."
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 In many ways microglia act as the Red Cross, he added. They can
converge upon sites of injury in the brain to scour away neuronal
debris and begin repairs, and during a peripheral infection the
cytokines they produce cause behavioral changes that support
convalescence and healing. However, if microglia overreact, the
result can be pathological.
Johnson's study, which was published in August, revealed that
older animals had an exaggerated inflammatory cytokine response in
the brain compared with young animals when the peripheral immune
system was stimulated with LPS.
"In the old animals, the message of a peripheral infection is
conveyed to the brain, but the cells in the brain have an
exaggerated response and produce more inflammatory cytokines than
what is typical," Johnson said. "The exaggerated response can lead
to a more intense and longer-lasting sickness behavior syndrome."
To study the phenomenon further, Johnson and colleagues examined
the expression of more than 39,000 genes in the brain using
microarray technology. The approach was helpful, because the gene
expression pattern indicated brain inflammation emerged during
aging. The emergence of a mild but chronic neuroinflammatory state
appears to have a priming effect on microglial cells, Johnson said.
"Chronic neurodegenerative diseases prime microglia so that when
an individual develops a peripheral infection, these cells overreact
and exacerbate neurodegenerative disease," he said. "Peripheral
infection is now recognized as a significant risk factor for relapse
for multiple sclerosis, for example, and peripheral infection is a
risk factor for delirium in Alzheimer's patients."
The research suggests that normal aging also may prime microglia,
Johnson said.
The six co-authors with Johnson on the study were postdoctoral
researcher Jonathan P. Godbout; research associate Jing Chen;
graduate students Jayne Abraham, Amy F. Richwine and Brian M. Berg;
and Keith W. Kelley, a professor of integrative immunology and
behavior in the Department of Animal Sciences.
Funding was provided by the National Institutes of Health.
Godbout, now a professor at Ohio State University, was supported by
a National Research Service Award from the National Institutes of
Health to the U. of I.'s Division of Nutritional Sciences.
[University of Illinois news
release by Molly McElroy] |
