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Natural Alzheimer's weapon suggests better
treatment
June 21, 2011 – Scientists
have shown a molecular chaperone is working
like a waste management company to collect
and detoxify high levels of toxic amyloid
beta peptide found in Alzheimer's disease.
It was known that the
molecular chaperone, HspB1, was present in
the hallmark plaque of Alzheimer's patients
but its role remained a mystery.
"What we have found is HspB1
is a protective mechanism that tries to get
rid of the toxic oligomers or aggregates of
amyloid beta that occur in Alzheimer's,"
said Dr. Anil G. Cashikar, Biochemist at
Georgia Health Sciences University's Center
for Molecular Chaperones and Radiobiology.
He is corresponding author of the study
published in Molecular and Cellular
Biology.
Amyloid beta peptide, or
Abeta, is believed to start the cascade of
events that leads to brain cell damage and
death in Alzheimer's: as levels increase,
the peptide starts clumping in the brain. In
fact, high levels in the spinal fluid are a
diagnostic marker for the disease.
Molecular chaperones are
known for their propensity to respond to
disease-producing misfolded proteins, which
is how the body views excessive Abeta.
While resulting plaques
occupy prime real estate in the brain, it's
still better than toxic Abeta killing
neurons, Cashikar said. "We think maybe the
system gets overwhelmed."
Acknowledging much work
remains, the scientist is excited about
identifying the protective mechanism and
exploring its treatment potential.
Earlier this year, a paper
Cashikar published in PLoS One showed
deleting genes with a similar function from
a mouse model of Alzheimer's worsened
disease symptoms. The new study also showed
neurons from HspB1-deficient mice were more
sensitive to the toxic ravages of Abeta.
"HspB1 is present because its
function is to protect cells. The
implication is if we can elevate the levels
of this molecular chaperone, we may be able
to handle the situation a little better,"
Cashikar said.
He wants to exploit this
natural system by developing a smaller
version of the molecular chaperone that
could be put into the bloodstream to leach
excess Abeta from the brain. The brain has a
natural protective mechanism that likely
would prevent its direct application.
However, the natural affinity
of amyloid beta and HspB1 indicates a more
distant approach could be effective.
"We want to come up with
smaller versions of HspB1 that can be put
into the bloodstream so you can sop up the
material from the brain into the blood where
it can be cleared more efficiently." He also
wants to explore a way to increase brain
cells' natural production of protective
HspB1.
Neurons actually also make
the Abeta believed to attack them in
Alzheimer's. The peptide's normal function
in the brain is not clear, but early
evidence suggests it could be involved in
synaptic pruning, which is essential for
memory formation.
Synapses connect neurons and
some existing connections must be cut for
new connections and memories to be made. Why
neurons start making too much Abeta and how
its overproduction can be controlled are
million-dollar questions, Cashikar said.
A related ongoing debate is
whether the amyloid plaques and
neurofibrillarly tangles, insoluble globs of
protein also found in Alzheimer's, are a
cause or result of the disease. Cashikar's
work as well as new studies on the
neurofibrillarly tangles, suggest both are
protective mechanisms. Also, there is
evidence of both in the brains of some
healthy, elderly individuals.
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