Alzheimer's, Dementia & Mental Health
Pericyte Brain Cells Found to be Possible Key
Players in Alzheimer’s, Other Diseases
Pericyte in a
surprising new role as a key player shaping blood flow in the brain and
protecting sensitive brain tissue from harmful substances
Nov. 17, 2010 -
Cells in the brain called pericytes that have not been high on the list
of targets for treating diseases like Alzheimer’s may play a more
crucial role in the development of neurodegenerative diseases than has
been realized.
The findings,
published in Neuron, cast the pericyte in a surprising new
role as a key player shaping blood flow in the brain and protecting
sensitive brain tissue from harmful substances. By manipulating pericyte
levels, scientists were able to re-create in the brains of mice an array
of abnormalities that mirror in striking fashion the brain difficulties
that occur in many people as they age.
“For 150 years
these cells have been known to exist in the brain, but we haven’t known
exactly what they are doing in adults,” said
Berislav Zlokovic, M.D., Ph.D., the neuroscientist who led the
research at the University of Rochester Medical Center.
“It turns out
that pericytes are very important for helping maintain a brain
environment crucial to the health of neurons. The pericyte offers us an
exciting new target for new treatments for neurodegenerative diseases.”
While damage to
neurons oftentimes causes the symptoms that patients experience –
dementia in Alzheimer’s, and movement difficulties in Parkinson’s
disease, for instance – neuroscientists know that neurons depend on a
broad variety of factors coming together to create just the right
environment to thrive.
Zlokovic has
pioneered the concept that impaired blood flow and flaws in the
blood-brain barrier may play a huge role in the development of diseases
like Alzheimer’s through their impact on neurons.
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Robert Bell |
Ethan Winkler |
Berislav Zlokovic |
In the most
recent findings from Zlokovic’s laboratory, the two first authors who
contributed equally to the research, graduate student Robert Bell and
M.D./Ph.D. student Ethan Winkler, teased out the role of the
pericyte in the process.
Pericytes ensheath the smallest blood vessels
in the brain, wrapping around capillaries like ivy wrapping around a
pipe and helping to maintain the structural integrity of the vessels.
It turns out that
pericytes do much more. The team found that the cells are central to
determining the amount of blood flowing in the brain and play an
instrumental role in maintaining the barrier that stops toxic substances
from leaking out of the capillaries and into brain tissue. When the team
reduced the number of working pericytes in the brains of mice, the
effects included reduced blood flow, greater exposure of brain tissue to
toxic substances, impaired learning and memory, and damage to the
neurons – all phenomena that are more likely to happen to people as they
age.
“This work shows
that other cells in the brain have a tremendous effect on the neurons,
even driving the neurodegenerative process,” said Winkler. “This is very
exciting.”
To make the
finding, the team studied mice in which the normal number of pericytes
is reduced dramatically. Scientists studied young mice (about one month
old), middle-aged mice (about six to eight months old), and older mice
(14 to 16 months old).
The amount of
damage that occurred depended on age, with the worst damage occurring
consistently in the oldest mice – a finding that parallels what happens
with people, whose brains are much more likely to suffer
neurodegenerative conditions like Alzheimer’s or Parkinson’s disease as
they age. The mice experienced an array of problems that match up pretty
closely with the brain abnormalities that people with neurodegenerative
conditions like Alzheimer’s experience.
Among the
findings in mice with reduced levels of pericytes:
●
Cerebral blood
flow was reduced, and the problem worsened as the mice got older. Older
mice had 50 percent less blood flow than mice of similar age with a
normal number of pericytes. Younger and middle-age mice had 23 percent
less and 33 to 37 percent less blood flow, respectively.
●
Serum proteins
and toxic molecules were much more likely to gain entry to the brain,
thanks to a breakdown of the blood-brain barrier. For instance,
molecules such as hemosiderin, fibrin, thrombin and plasmin are toxic in
the brain and are normally not found in brain tissue. The older mice had
20 to 25 times as much accumulation of these toxins in their brain
tissue as their normal counterparts; the younger and middle-age mice had
three times as much and 8 to 10 times as much, respectively.
●
The breakdown in
the blood-brain barrier was especially evident in blood vessel
structures known as tight junctions, which play an important role in
stopping harmful substances from reaching brain tissue. Their activity
in the older mice was down 40 to 60 percent in older and middle-age mice
compared to their normal counterparts.
●
Compared to
normal mice, the mice with fewer pericytes had structural damage to
their neurons, including loss of dendritic length and spine density.
Again, the amount of damage correlated to the age of the mice, with
older mice showing more damage. The team also documented impaired
learning and memory in the middle-age and the older mice, but not the
youngest mice.
“Our findings
show that chronic vascular damage due to pericyte loss results in
neurodegeneration,” said Zlokovic, who is Dean’s Professor in the
Departments of Neurosurgery and
Neurology and director of the
Center for Neurodegenerative and Vascular Brain Disorders.
“It may
be that a vascular insult is common to many different types of
neurodegenerative processes and may be significant in causing the
symptoms seen in diseases such as Alzheimer’s and amyotrophic lateral
sclerosis.”
The findings
could cause neuroscientists to change their views of the origins of many
neurodegenerative disorders, said Bell, who notes that a recently
developed tool to track pericyte activity in the brain helped the team
tackle the role of the pericyte.
“If all your
tools are designed to study neurons, you’ll learn a lot about neurons,”
Bell said. “We haven’t known much about pericytes simply because we
haven’t had good tools to watch them. If you can’t see the cells, it is
difficult to study them.”
In addition to
Bell, Winkler, and Zlokovic, other authors include Abhay Sagare, Ph.D.,
senior instructor; Rashid Deane, Ph.D., research professor; Itender
Singh, Ph.D., postdoctoral research associate; and Barbra LaRue,
technical associate. The project was funded by the National Institute on
Aging (grant # R37AG023084) and the National Institute of Neurological
Disorders and Stroke (grant # R37NS34467).
Zlokovic is the
founder of and an equity holder in three companies exploring new
treatments for stroke and neurodegenerative diseases like Alzheimer’s:
Socratech, ZZ Alztech, and ZZ Biotech. The University of Rochester
holds an equity interest in all three companies as well.
The research was
published Nov. 4 in Neuron
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Pericyte - definition in Medical dictionary
