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Alzheimer's: New findings Resolve long
dispute about how the Disease might kill
Brain Cells
Newswise — For a decade, Alzheimer's disease
researchers have been entrenched in debate
about one of the mechanisms believed to be
responsible for brain cell death and memory
loss in the illness.
Now researchers at the University of
Michigan and the University of California,
San Diego have settled the dispute.
Resolving this controversy improves
understanding of the disease and could one
day lead to better treatments.
Michael Mayer, an assistant professor in the
U-M departments of Biomedical Engineering
and Chemical Engineering, and Jerry Yang, an
assistant professor in the Department of
Chemistry and Biochemistry at UCSD, and
their colleagues found a flaw in earlier
studies supporting one side of the debate.
Their findings are published online in the
journal Neurotoxicity Research. They will
appear in the May print edition.
Their results clarify how small proteins
called amyloid-beta peptides damage brain
cell membranes, allowing extra calcium ions
to enter the neurons.
An ion is an electrically-charged particle.
An ion imbalance in a cell can trigger its
suicide.
Amyloid-beta peptides are the prime suspects
for causing cell death in Alzheimer's,
although other mechanisms could also be to
blame.
The disease is not well understood.
The researchers confirmed evidence found by
others that amyloid-beta peptides prick
pores into brain cell membranes, opening
channels where calcium ions can rush in.
This was one mechanism the field had
contemplated, but other evidence suggested a
different scenario.
Some researchers believed that the peptide
caused a general thinning of the cell
membranes and these thinned membranes lost
their ability to keep calcium ions out of
brain cells.
Mayer and Yang disproved this latter theory.
"When you understand these mechanisms
better, you have a better chance of being
able to pharmaceutically counteract them as
a possible treatment.
"For
instance, if amyloid-beta thins membranes,
this general effect might be difficult to
treat. On the other hand, if it forms pores,
this effect might be treatable with pore
blockers.
"Ion
channel blockers are medications sold today
to treat a variety of diseases," Mayer said.
He cautions that much research is needed
before it is known whether such medications
are effective and safe to treat Alzheimer's.
Mayer and Yang were able to explain the
other experimental results that blamed cell
membrane thinning for uncontrolled calcium
ion fluctuations.
It turns out that in these studies, trace
amounts of residual solvent used to prepare
the peptide had a dramatic effect.
The Michigan- and UCSD-led team reproduced
these experimental results using only the
solvent, without the peptide.
The solvent is called Hexafluoroisopropanol,
or HFIP.
"HFIP is a good solvent used to break up
clumps of the peptide to prepare for
experiments but it's toxic and
membrane-active.
"What
we found was that the reported preparation
procedure did not remove the solvent
effectively," Mayer said.
"Our findings are watertight since we could
reproduce the thinning effect in the absence
of amyloid-beta peptides by this solvent
alone."
Yang and Mayer carried out these experiments
by examining how the electric current
fluctuates across artificial membranes and
live human cancer cell membranes in the
presence of the amyloid-beta peptide.
(Cancer cells are often used in biological
experiments because they reproduce rapidly.)
They also measured the fluctuation of ions
in mouse brain cells and in
genetically-modified mouse brain cells that
produce human amyloid-beta peptide.
In all these trials, the electrodes
measuring across the cell membrane
registered spikes in electric current
consistent with what researchers would
expect from the formation of pores in the
cell membrane and not from thinning of
membranes.
"This ongoing controversy has slowed our own
progress in Alzheimer's research as well as
progress in other labs," Mayer said.
"It is our hope that putting this
disagreement to rest by showing that amyloid
beta peptides do not thin membranes but
instead form discrete pores in membrane can
help the field move forward at a more rapid
pace."
The paper is called "Amyloid-beta-induced
ion flux in artificial lipid bilayers and
neuronal cells: Resolving a controversy."
Members of Mayer's and Yang's research
groups contributed to this study, as did the
research group of R. Scott Turner, an
associate professor of neurology at the U-M
Medical School.
The research is funded by the Wallace H.
Coulter Foundation, the National Science
Foundation, the Alzheimer's Disease Research
Center and the Alzheimer's Association.
U-M has filed for patent protection on this
research, and it is seeking licensing
partners to help bring the technology to
market.
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