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Compounds have potential for diagnosis, treatment of
Alzheimer's Disease
Newswise — New research
suggests that a select group of compounds
that interact with a protein in the brain
might be used in the early diagnosis and
treatment of Alzheimer’s disease and other
dementia disorders.
Scientists have discovered
that these compounds interact in three
specific ways with the tau protein, which is
the subject of a growing body of research
into the causes and progression of dementia.
In a normal, healthy brain,
the tau protein binds to and stabilizes
structures in the brain that are essential
for proper functioning.
But tau protein that breaks
away from these structures can begin forming
long strands called filaments. These
filaments can clump into tangles, which are
a marker of Alzheimer’s disease and other
neurodegenerative disorders.
Depending on the specific
compounds under study, they can produce
three different outcomes when introduced to
the tau protein: They either bind to the
protein filaments; inhibit the filaments
from developing; or drive tau protein to
form filaments.
So far, the interactions have
been observed in test tubes and cell
cultures, so any clinical use of the
compounds will require years of additional
research.
All three interactions are
expected to increase scientists’
understanding of the neurodegenerative
disease process, said Nicolette Honson, a
postdoctoral researcher in the Center for
Molecular Neurobiology at Ohio State
University.
But certain compounds seem to
show potential to allow for earlier
diagnosis of Alzheimer’s and other
neurodegenerative disorders because of their
tendency to seek out and stick to tau
filaments, Honson said.
“It’s important now to find
compounds that can be used in imaging
because the earlier clinicians can detect
the disease, the better the chances are that
a drug will halt disease progression while
patients still have strong cognitive
abilities,” she said.
Honson described the research
at the American Chemical Society meeting in
Philadelphia.
Currently, images of the
brain that can detect Alzheimer’s disease
use compounds designed to locate another
marker of dementia: plaques of the peptide
amyloid beta. Both these plaques and tangles
are present in the brains of people with
certain dementia disorders.
Researchers are engaged in a
debate about whether the plaques and tangles
are mere markers of disease or actually have
a role in causing neurodegenerative diseases
to progress.
So far, they know the
presence of tau tangles can occur in the
human brain many years before any cognitive
decline is apparent.
Alzheimer’s disease is the
most common form of dementia among older
people. It initially involves the parts of
the brain that control thought, memory and
language.
The cause is unknown and
there is no cure. An estimated 4.5 million
Americans suffer from Alzheimer’s, according
to the National Institute on Aging.
Honson and colleagues, led by
Jeff Kuret, professor of molecular and
cellular biochemistry at Ohio State, plan to
test binding compounds on donated human
brain tissue made available for research.
The scientists will add the
compounds to sections of brain tissue from
Alzheimer’s disease patients and to healthy
brain tissue to test whether the compounds
continue to stick to tau tangles under the
conditions present in a diseased brain.
Another family of compounds
the researchers studied was able to stop tau
from forming filaments, hinting at the
compounds’ potential as a basis for
therapies to treat dementia diseases
characterized by the formation of tau
tangles.
“When we added these
compounds to the reaction, their interaction
with the tau protein inhibited filaments
from forming, which could be valuable for
therapeutics because it would prevent the
formation of tau tangles.
"Some
people think if we clear away the pathology
seen in diseased brains, that might
alleviate symptoms of Alzheimer’s disease,”
Honson said.
These compounds will be
tested in mice that have been genetically
modified to have the characteristics of
dementia to see if the compounds have
similar inhibiting effects in an animal
model.
A third finding of a family
of compounds that can cause tau protein to
form filaments will allow scientists to
study the disease process.
Honson noted that she and
colleagues could induce filament formation
with these compounds and then use that
induced disease model to test the compounds
that might be able to stop the disease from
progressing.
The researchers began their
search by screening 70,000 compounds
contained in the Molecular Library Screening
Center Network of the National Institutes of
Health (NIH).
Honson and Kuret conducted
this research with Bhaswati Bandyopadhyay, a
former postdoctoral researcher at Ohio
State, and Edward Chang, Swati Naphade and
Jordan Jensen, all graduate students in Ohio
State’s Center for Molecular Neurobiology.
The NIH and the Alzheimer’s
Association funded the research.
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