Salk scientists show how immune receptors clear dead
and dysfunctional brain cells and how they might be targets for treating neurodegenerative
diseases
Newswise, April 7, 2016-By adolescence, your brain
already contains most of the neurons that you'll have for the rest of your
life. But a few regions continue to grow new nerve cells--and require the
services of cellular sentinels, specialized immune cells that keep the brain
safe by getting rid of dead or dysfunctional cells.
Now, Salk scientists have uncovered the surprising
extent to which both dying and dead neurons are cleared away, and have
identified specific cellular switches that are key to this process.
"We discovered that receptors on immune cells
in the brain are vital for both healthy and injured states," says Greg
Lemke, senior author of the work, a Salk professor of molecular neurobiology
and the holder of the Françoise Gilot-Salk Chair.
"These receptors could be potential therapeutic
targets for neurodegenerative conditions or inflammation-related disorders,
such as Parkinson's disease."
Two decades ago, the Lemke lab discovered that
immune cells express critical molecules called TAM receptors, which have since
become a focus for autoimmune and cancer research in many laboratories.
Two of the TAM receptors, dubbed Mer and Axl, help
immune cells called macrophages act as garbage collectors, identifying and
consuming the over 100 billion dead cells that are generated in a human body
every day.
For the current study, the team asked if Mer and Axl
did the same job in the brain. Specialized central nervous system macrophages
called microglia make up about 10 percent of cells in the brain, where they
detect, respond to and destroy pathogens.
The researchers removed Axl and Mer in the microglia
of otherwise healthy mice. To their surprise, they found that the absence of
the two receptors resulted in a large pile-up of dead cells, but not everywhere
in the brain.
Cellular corpses were seen only in the small regions
where the production of new neurons--neurogenesis--is observed.
Many cells die normally during adult neurogenesis,
but they are immediately eaten by microglia.
"It is very hard to detect even a single dead
cell in a normal brain, because they are so efficiently recognized and cleared
by microglia," says Paqui G. Través, a co-first author on the paper and
former Salk research associate. "But in the neurogenic regions of mice
lacking Mer and Axl, we detected many such cells."
When the researchers more closely examined this
process by tagging the newly growing neurons in mice's microglia missing Mer
and Axl, they noticed something else interesting.
New neurons that migrate to the olfactory bulb, or
smell center, increased dramatically without Axl and Mer around. Mice lacking
the TAM receptors had a 70 percent increase in newly generated cells in the
olfactory bulb than normal mice.
How--and to what extent--this unchecked new neural
growth affects a mouse's sense of smell is not yet known, according to Lemke,
though it is an area the lab will explore.
But the fact that so many more living nerve cells
were able to migrate into the olfactory bulb in the absence of the receptors
suggests that Mer and Axl have another role aside from clearing dead
cells--they may actually also target living, but functionally compromised,
cells.
"It appears as though a significant fraction of
cell death in neurogenic regions is not due to intrinsic death of the cells but
rather is a result of the microglia themselves, which are killing a fraction of
the cells by engulfment," says Lemke.
"In other words, some of these
newborn neuron progenitors are actually being eaten alive."
This isn't necessarily a bad thing in the healthy
brain, Lemke adds. The brain produces more neurons than it can use and then
prunes back the cells that aren't needed. However, in an inflamed or diseased
brain, the destruction of living cells may backfire.
The Lemke lab did one more series of experiments to
understand the role of TAM receptors in disease: they looked at the activity of
Axl and Mer in a mouse model of Parkinson's disease.
This model produces a human protein present in an
inherited form of the disease that results in a slow degeneration of the brain.
The team saw that Axl was far more active in this setting, consistent with
other studies showing that increased Axl is a reliable indicator of
inflammation in tissues.
But the researchers were in for a surprise when they
removed Axl and Mer from the Parkinson's mice. Instead of being worse off
compared to mice with the disease but with normal microglia, the mice missing
Axl and Mer actually lived longer.
This may be because Axl and Mer target and destroy
sick, dysfunctional neurons. In the presence of disease, there could be more
dysfunctional neurons than normal, so Axl and Mer may be prompting the
destruction of too many neurons, in effect hastening the disease.
"It seems that we can modify the course of the
disease in an animal model by manipulating Axl and Mer," says Lawrence
Fourgeaud, a co-first author on the paper and former Salk research associate.
The team cautions that more research needs to be done to determine if
modulating the TAM receptors could be a viable therapy for neurodegenerative
disease involving microglia.
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Other researchers on the paper were Yusuf Tufail,
Humberto Leal-Bailey, Erin D. Lew, Patrick G. Burrola, Perri Callaway, Anna
Zagórska and Axel Nimmerjahn of the Salk Institute; and Carla V. Rothlin of the
Yale University School of Medicine.
The work was supported by the National Institutes of
Health, the Leona M. and Harry B. Helmsley Charitable Trust, the Howard Hughes
Medical Institute, and the Nomis, H.N. and Frances C. Berger, Fritz B. Burns,
HKT, Waitt, Rita Allen, and Hearst foundations.
About the Salk Institute for Biological Studies:
Every cure has a starting point. The Salk Institute
embodies Jonas Salk's mission to dare to make dreams into reality. Its
internationally renowned and award-winning scientists explore the very
foundations of life, seeking new understandings in neuroscience, genetics,
immunology and more. The Institute is an independent nonprofit organization and
architectural landmark: small by choice, intimate by nature and fearless in the
face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is
where cures begin. Learn more at: salk.edu.
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