Could leaky blood vessels in the brain be a culprit in Alzheimer's
disease?
Date:
March 10, 2022
Source:
Medical University of South Carolina
Summary:
Researchers report that they found high levels of the protein Fli-1
in the brains of deceased Alzheimer's patients. Blocking Fli-1's
action in a mouse model of Alzheimer's disease reversed mental loss
and reduced the brain inflammation and amyloid-beta clumping that
are hallmarks of Alzheimer's disease. Although clinical translation
of this finding is likely years off, the study suggests Fli-1 is
a promising therapeutic target for Alzheimer's disease.
FULL STORY ========================================================================== Alzheimer's disease is an enormous problem that, with an aging population,
will only get bigger. More than 6 million Americans are living with
Alzheimer's disease, and 1 in 3 seniors will die of it, according to
the Alzheimer's Association. By 2050, the cost of Alzheimer's disease, currently estimated at $355 billion, will rise to $1.1 trillion.
========================================================================== Could one of the causes of such a huge and costly problem be traced back
to the cells that line the body's tiniest blood vessels? A new study
published by a Medical University of South Carolina (MUSC) research team
in Molecular Therapy suggests that the answer is yes. The team, led by
Hongkuan Fan, Ph.D., associate professor in the Department of Pathology
and Laboratory Medicine, found fewer of these cells, known as pericytes,
in the brains of people who died of Alzheimer's disease. They also found
higher levels of Fli-1, a protein most often found in blood cells and
thought to govern their development.
When the team blocked, or inhibited, the action of Fli-1 in a mouse model
of Alzheimer's disease, the memory of the mice improved. Blocking the
protein also stopped immune cells from leaking into the brain and causing
the inflammation that is a hallmark of Alzheimer's disease. Blocking
Fli-1 could be a promising new approach to treating Alzheimer's disease
and other dementias.
"We are really excited by these data because they suggest that Fli-1
could be a new therapeutic target for Alzheimer's disease," said Fan.
Better therapies for Alzheimer's disease are urgently needed. Most
existing Alzheimer's therapies just treat the symptoms and do little to
address underlying causes.
==========================================================================
It has long been known that people who have vascular issues, or problems
with their hearts or blood vessels, are at increased risk of developing Alzheimer's disease and other dementias. These include people who have had
a heart attack or who have diabetes or high blood pressure or cholesterol.
That's not surprising, since the brain is hungry for oxygen. When it
doesn't get enough, because the flow of blood is inadequate, its cells
don't function as well and can begin to die.
Lining the walls of tiny blood vessels known as capillaries, pericytes
make sure the brain's energy and waste-elimination demands are met.
"The capillary is where all the action is," said Perry Halushka,
M.D., Ph.D., Distinguished University Professor of Cell and Molecular Pharmacology. "It is the place where all these exchanges really take
place." Pericytes also help to make up the blood-brain barrier that
prevents impurities and immune cells in the blood from reaching the
brain. They also help to remove amyloid-beta, known to be a culprit in Alzheimer's disease, from the brain.
==========================================================================
When pericytes are lost, immune cells and impurities begin to leak into
the brain, causing it to become inflamed and eventually leading to cell
death and declining mental function.
"Pericytes may play a much more important role in dementia than people originally thought," said Halushka. "This is especially true in the aging population, where vascular dementia is going to become a bigger problem."
With funding from the South Carolina Clinical & Translational Research Institute, the MUSC team looked at the brains of people who had died of Alzheimer's disease, drawing on the resources of the brain bank at the
Carroll A. Campbell, Jr. Neuropathology Laboratory.
"The opportunity to study the human brain is an extraordinary asset
for the institution and for the study of all types of brain diseases,
not just Alzheimer's disease," said Halushka.
The MUSC team found that the brains of people who died of Alzheimer's
disease had 34% fewer pericytes than healthy brains in their hippocampus,
a part of the brain associated with learning and memory. The remaining pericytes had much higher levels of Fli-1.
The team then showed that an animal model of Alzheimer's also showed
pericyte loss in the hippocampus, increased Fli-1 and impaired
memory. Blocking Fli- 1 improved the mice's performance on behavioral
tests meant to assess memory.
"The most exciting finding is that the Fli-1 inhibitor actually improved cognitive deficits in the animal model because, in the end, that's the
only thing that matters," said Halushka.
The team also found that blocking Fli-1 in the mice helped to prevent
pericyte loss and preserve the integrity of the blood-brain barrier as
well as reduce the build-up of amyloid-beta.
"We didn't expect such a profound effect in the mice, but to our surprise,
the inhibitor really worked," said Fan.
The next step for the MUSC team is to develop an RNA that could silence
Fli- 1 and so reduce the brain inflammation that leads to cell death in Alzheimer's disease. The goal would not be to do away with Fli-1, as it
serves important roles in the body, but to maintain it at healthy levels.
"What's exciting is that this could be a new way to think about
treating Alzheimer's disease, which has never been thought of before,"
said Halushka.
"This research opens up a whole new area for potential targets, not just
Fli- 1 but the pericyte itself."
========================================================================== Story Source: Materials provided by
Medical_University_of_South_Carolina. Original written by Kimberly
McGhee. Note: Content may be edited for style and length.
========================================================================== Journal Reference:
1. Pengfei Li, Yan Wu, Eric D. Hamlett, Andrew J. Goodwin, Perry V.
Halushka, Steven L. Carroll, Meng Liu, Hongkuan Fan. Suppression
of Fli- 1 protects against pericyte loss and cognitive
deficits in Alzheimer's disease. Molecular Therapy, 2022; DOI:
10.1016/j.ymthe.2022.01.023 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220310115057.htm
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