Discovery Advances Battle Against Disease That
Strikes 1 in 9 People Over 65
IN
SUMMARY:
- UVA scientists have mapped out how a
toxic protein spreads through the brain in Alzheimer’s
disease. - Findings explain what triggers the
protein’s accumulation and how it harms nerve cells called
neurons. - Research advances efforts to develop blood
tests to detect Alzheimer’s at its earliest stages —
long before symptoms appear.
CHARLOTTESVILLE,
Va., January 12, 2023 – Tau protein is notorious for
forming tangles in the brains of people with Alzheimer’s
disease and several other neurodegenerative disorders, and
for helping to cause cognitive decline associated with those
diseases. University of Virginia neuroscientists have
revealed how a toxic form of tau spreads through the brain
as the disease progresses, what provokes its accumulation
and how it harms nerve cells called neurons. Scientists may
be able to leverage these findings to develop new
Alzheimer’s treatments that prevent or delay symptom
onset, or slow disease progression once symptoms
develop.
UVA’s new research also advances efforts to
develop blood tests to detect Alzheimer’s at its earliest
stages, when it is, in principle, most amenable to
treatment. The researchers found that antibodies used in
blood tests for measuring this toxic, chemically modified
form of tau, taupT217, can easily be fooled into detecting
other proteins, which compromises test accuracy.
Fortunately, they also showed how this problem can be
avoided.
The new research from UVA’s George Bloom,
PhD, and collaborators is the most comprehensive examination
yet of where and how taupT217 accumulates in the brain. The
results provide vital insights into the development of
Alzheimer’s and possibly other neurological conditions
called “non-Alzheimer’s tauopathies,” which include
Parkinson’s disease and chronic traumatic
encephalopathy.
“The past few years have witnessed
exciting advances in early Alzheimer’s detection by
measuring the amount of taupT217 in blood or cerebrospinal
fluid, but until now almost nothing has been learned about
what causes this type of tau to form in the brain or how it
affects neuron health,” said Bloom, of UVA’s Departments
of Biology, Cell Biology and Neuroscience, as well as the
UVA Brain Institute, the Virginia Alzheimer’s Disease
Center and UVA’s Program in Fundamental Neuroscience.
“Knowing what provokes taupT217 to build up in the brain
and how it harms neurons provides new openings for
therapeutic intervention.”
Understanding
Alzheimer’s
Tau plays important roles in the
healthy brain, where, among other things, it helps build and
maintain the “microtubules” that serve as highways for
transporting important materials within the neurons that
form the brain’s circuitry. But in people with
Alzheimer’s, tau becomes chemically modified and misshapen
in ways that prevent its normal functioning and make it
toxic. This eventually leads to two phenomena that account
for cognitive decline in Alzheimer’s: destruction of
neuronal circuitry and neuron death.
Why this occurs
has been only partially understood, but UVA’s new research
offers more answers. For example, the researchers found that
they could trigger taupT217 buildup inside cultured neurons
by exposing them to clusters, or oligomers, of tau, which
are known to accumulate in the Alzheimer’s brain and have
long been suspected as a harmful contributor to the disease.
They also found that the chemical modification that converts
normal tau into taupT217 dramatically decreases tau’s
ability to stick to microtubules, which in turn may make it
easier for the tau to form toxic oligomers.
“In
terms of immediate clinical value, we hope that our findings
about the challenge of antibody specificity for measuring
taupT217 in blood will quickly resonate with companies that
are striving to develop commercially available tests to
identify Alzheimer’s patients years before symptoms become
evident,” Bloom said. “Because massive irreversible
brain damage has already occurred by symptom onset, accurate
early diagnosis will be crucial for development of drugs
that effectively combat Alzheimer’s.”
That’s
just one example of the practical insights generated by
UVA’s research that will benefit the efforts to better
diagnose and treat Alzheimer’s.
“Alzheimer’s
disease reflects a multi-dimensional breakdown of normal
brain cells, so there is nothing simple about it,” Bloom
said. “Focusing research on the earliest processes that
convert normal brains into Alzheimer’s brains, though,
provides the best hope for eventually conquering this
terrible disease.”
Findings Published
The
researchers have published their findings in the scientific
journal Alzheimer’s & Dementia. The first author of
the paper is Binita Rajbanshi, a recently graduated
pharmacology PhD student. The other team members were Anuj
Guruacharya, James Mandell and Bloom. The scientists
reported that they have no financial interests in the
work.
The research was supported by The Owens Family
Foundation, the Cure Alzheimer’s Fund, the Rick Sharp
Alzheimer’s Foundation, the National Institutes of Health
(grant RF1 AG051085), and Webb and Tate
Wilson.
MORE ON ALZHEIMER’S FROM
UVA: Discovery
holds key to boosting brain’s ability to battle
Alzheimer’s, MS.
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