Blood from marathoner mice boosts brain function in their couch-potato counterparts

Date:
December 8, 2021
Source:
Stanford Medicine
Summary:
Researchers have shown that blood from young adult mice that
are getting lots of exercise benefits the brains of same-aged,
sedentary mice. A single protein in the blood of exercising mice
seems largely responsible for that benefit.



FULL STORY ========================================================================== Physical exercise is great for a mouse's brain, and for yours. Numerous
studies conducted in mice, humans and laboratory glassware have made
this clear. Now, a new study shows it's possible to transfer the brain
benefits enjoyed by marathon-running mice to their couch-potato peers.


========================================================================== Stanford School of Medicine researchers have shown that blood from young
adult mice that are getting lots of exercise benefits the brains of
same-aged, sedentary mice. A single protein in the blood of exercising
mice seems largely responsible for that benefit.

The discovery could open the door to treatments that -- by taming brain inflammation in people who don't get much exercise -- lower their risk
of neurodegenerative disease or slow its progression.

In the study, to be published Dec. 8 in Nature, the Stanford researchers compared blood samples from exercising and sedentary mice of the same
age. They showed that transfusions of blood from running mice reduced neuroinflammation in the sedentary mice and improved their cognitive performance. In addition, the researchers isolated a blood-borne protein
that appears to play an important role in the anti-neuroinflammatory
exercise effect.

Inflammation and cognitive health Neuroinflammation has been strongly
tied to neurodegenerative diseases in humans, said Tony Wyss-Coray,
PhD, professor of neurology and neurological sciences. Animal studies
have indicated that neuroinflammation precipitates neurodegenerative
disorders and that reversing or reducing neuroinflammation can prolong cognitive health, he said.



========================================================================== Anybody who's suffered from influenza can relate to the loss of cognitive function that comes from a fever-inducing viral infection, Wyss-Coray
said: "You get lethargic, you feel disconnected, your brain doesn't work
so well, you don't remember as clearly." That's a result, at least
in part, of the bodywide inflammation that follows the infection. As
your immune system ramps up its fight, the inflammation spills over
into your brain. Neuroinflammation also exacerbates the progression of Alzheimer's and other neurodegenerative diseases, said Wyss-Coray, a
neuro- immunologist who in a study published earlier this year identified
signs of brain inflammation in people who had died of COVID-19.

Wyss-Coray is the new study's senior author. The lead author is Zurine De Miguel, PhD, a former postdoctoral scholar in Wyss-Coray's group who is
now an assistant professor of psychology at California State University, Monterey Bay.

It's already known that exercise induces a number of healthy
manifestations in the brain, such as more nerve-cell production and
less inflammation.

"We've discovered that this exercise effect can be attributed to a large
extent to factors in the blood, and we can transfer that effect to a
same-aged, non- exercising individual," said Wyss-Coray, the D. H. Chen Professor II.



========================================================================== Nightly mouse marathon Mice love to run. Give a caged mouse access to a
running wheel a few inches in diameter and, with no training or prompting,
it will rack up 4 to 6 miles a night (they sleep by day) on legs that
are much shorter than ours. If you lock the wheel, the mouse won't log
nearly as much exercise, although it's still free to skitter hither and
thither about its cage (roughly equivalent to heading into the kitchen
now and then to fetch a beer or a snack from the fridge).

The investigators put either functional or locked running wheels into
the cages of 3-month-old lab mice, which are metabolically equivalent to 25-year-old humans. A month of steady running was enough to substantially increase the quantity of neurons and other cells in the brains of
marathoner mice when compared with those of sedentary mice.

Next, the researchers collected blood from marathoner and, as controls, sedentary mice. Then, every three days, they injected other sedentary
mice with plasma (the cell-free fraction of blood) from either marathoner
or couch-potato mice. Each injection equaled 7% to 8% of the recipient
mouse's total blood volume. (An equivalent amount in humans would be about
1/2 to 3/4 of a pint.) "The mice getting runner blood were smarter," Wyss-Coray said. On two different lab tests of memory, sedentary mice
injected with marathoner plasma outperformed their equally sedentary
peers who received couch-potato plasma.

In addition, sedentary mice receiving plasma from marathoner mice had
more cells that give rise to new neurons in the hippocampus (a brain
structure associated with memory and navigation) than those given
couch-potato plasma transfusions.

The scientists compared activation levels of thousands of genes in the hippocampus of sedentary mice receiving marathoner versus those receiving couch-potato plasma. Of the roughly 2,000 genes whose activation levels
changed in response to marathoner plasma, the 250 whose activation
levels changed most prominently were known to be most strongly linked to inflammatory processes, and their activation-level changes suggested lower neuroinflammation among mice who received marathoner-blood transfusions.

"The runners' blood was clearly doing something to the brain, even though
it had been delivered outside the brain, systemically," said Wyss-Coray.

Turning to an examination of proteins in the marathoner mice's blood,
the Stanford team identified 235 distinct proteins, of which 23 were
scarcer and 26 more abundant in marathoner compared with couch-potato
mice. Several of these differentially expressed proteins were associated
with the complement cascade - - a set of about 30 blood-borne proteins
that interact with one another to kick-start the immune response to
pathogens. Chronic inflammation resulting from aberrant activation
of the complement system, Wyss-Coray noted, appears to accelerate the progression of many neurodegenerative disorders.

A protein of interest Removing a single protein, clusterin, from
marathoner mice's plasma largely negated its anti-inflammatory effect
on sedentary mice's brains. No other protein the scientists similarly
tested had the same effect.

Clusterin, an inhibitor of the complement cascade, was significantly
more abundant in the marathoners' blood than in the couch potatoes' blood.

Further experiments showed that clusterin binds to receptors that abound
on brain endothelial cells, the cells that line the blood vessels of
the brain.

These cells are inflamed in the majority of Alzheimer's patients, noted
Wyss- Coray, whose research has shown that blood endothelial cells
are capable of transducing chemical signals from circulating blood,
including inflammatory signals, into the brain.

Clusterin by itself, even though administered outside the brain, was
able to reduce brain inflammation in two different strains of lab mice in
which either acute bodywide inflammation or Alzheimer's-related chronic neuroinflammation had been induced.

Separately, the investigators found that at the conclusion of a six-month aerobic exercise program, 20 military veterans with mild cognitive
impairment, a precursor to Alzheimer's disease, had elevated clusterin
levels in their blood.

Wyss-Coray speculated that a drug that enhances or mimics clusterin's
binding to its receptors on brain endothelial cells might help slow the
course of neuroinflammation-associated neurodegenerative diseases such
as Alzheimer's.

Wyss-Coray is a member of the Stanford Wu Tsai Neuroscience Institute,
Stanford Bio-X, and the Stanford Maternal and Child Health Research
Institute; and a faculty fellow of Stanford ChEM-H.

Other Stanford study co-authors are former postdoctoral scholars Nathalie Khoury, PhD, Niclas Olsson, PhD, Ryan Vest, PhD, and Hui Zhang, PhD;
former graduate student Michael Betley, DVM, PhD; former neurology
instructor Benoit Lehallier, PhD; former undergraduate Drew Willoughby; postdoctoral scholars Andrew Yang, PhD, Oliver Hahn, PhD, and Nannan
Lu, PhD; former medical and graduate student Liana Bonanno, MD, PhD;
Palo Alto Veterans Institute for Research assistant Lakshmi Yerra;
former staff scientist Lichao Zhang, PhD; laboratory manager Nay Lui
Saw; former life sciences research associate Davis Lee; Kaci Fairchild,
PhD, clinical assistant professor of psychology; former life science
research professional Patrick McAlpine; Mehrdad Shamloo, PhD, professor
of neurosurgery; Joshua Elias, PhD, assistant professor of chemical and
systems biology; and Thomas Rando, MD, PhD, professor of neurology and neurological sciences.

The study was funded by the National Institutes of Health (grants
AG0047820 and 1F32AG067652), the Stanford Alzheimer's Disease Research
Center (NIH grant P30 AG066515), the U.S. Department of Veterans Affairs,
the U.S. Department of Defense, the Alzheimer's Association and the Marie
Curie Foundation, the NOMIS Foundation, the Simons Foundation and the Wu
Tsai Neurosciences Institutes' Brain Rejuvenation Project with support
from the Bertarelli Foundation Stanford's Department of Neurology and Neurological Sciences also supported the work.

========================================================================== Story Source: Materials provided by Stanford_Medicine. Original written
by Bruce Goldman.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Zurine De Miguel, Nathalie Khoury, Michael J. Betley, Benoit
Lehallier,
Drew Willoughby, Niclas Olsson, Andrew C. Yang, Oliver Hahn, Nannan
Lu, Ryan T. Vest, Liana N. Bonanno, Lakshmi Yerra, Lichao Zhang,
Nay Lui Saw, J. Kaci Fairchild, Davis Lee, Hui Zhang, Patrick
L. McAlpine, Ke'vin Contrepois, Mehrdad Shamloo, Joshua E. Elias,
Thomas A. Rando, Tony Wyss- Coray. Exercise plasma boosts memory
and dampens brain inflammation via clusterin. Nature, 2021; DOI:
10.1038/s41586-021-04183-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211208122839.htm

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