Could this be the root cause of Alzheimer’s Disease?
From: Medical University of South Carolina
By Kimberly McGhee
March 9, 2022 -- Alzheimer’s
disease is an enormous problem that, with an aging population, will only become
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.”
https://web.musc.edu/about/news-center/2022/03/09/new-alzheimers-target
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