-
- Posted Friday January 15, 2010
Researchers identify proteins that might contribute to memory loss and Alzheimer's disease
TGen-led team finds 3 proteins that dismantle 'bridges' within
brain cells
PHOENIX, Ariz. - Jan. 15, 2009 - A scientific group led by the
Translational Genomics Research Institute (TGen) have identified
three kinases, or proteins, that dismantle connections within brain
cells, which may lead to memory loss associated with Alzheimer's
disease.
These findings, the results of a multi-year TGen study, are
published in this month's edition of BMC Genomics in a paper
titled: High-content siRNA screening of the kinome identifies
kinases involved in Alzheimer's disease-related tau
hyperphosphorylation.
The three kinases were found to cause a malfunction in tau, a
protein critical to the formation of the microtubule bridges within
brain cells, or neurons. These bridges support the synaptic
connections that, like computer circuits, allow neurons to
communicate with each other.
"The ultimate result of tau dysfunction is that neurons lose their
connections to other neurons, and when neurons are no longer
communicating, that has profound effects on cognition - the ability
to think and reason,'' said Dr. Travis Dunckley, an Associate
Investigator in TGen's Neurodegenerative Research Unit and the
scientific paper's senior author.
Tau performs a critical role in the brain by helping bind together
microtubules, which are sub-cellular structures that create
scaffolding in the neurons, allowing them to stretch out along
bridges called axons. The axons support the synaptic, or chemical,
connections with other neurons.
Under normal circumstances, kinases regulate tau by adding
phosphates. This process, called tau phosphorylation, enables the
microtubules to unbind and then bind again, allowing brain cells to
connect and reconnect with other brain cells.
"That facilitates synaptic plasticity. It facilitates the ability
of people to form new memories - to form new connections between
different neurons - and maintain those memories. So, it's an
essential function,'' Dr. Dunckley said.
However, sometimes the tau protein becomes hyperphosphorylated, a
condition in which the tau creates neurofibrillary tangles, one of
the signature indicators of Alzheimer's.
"When tau protein is hyperphosphorylated, the microtubule comes
apart - basically destroying that bridge - and the neurons can no
longer communicate with each other,'' Dr. Dunckley said.
TGen investigators created sophisticated tests to look at all 572
known and theoretical kinases within human cells. They identified
26 associated with the phosphorylation of tau. Of these 26, three
of them - EIF2AK2, DYRK1A and AKAP13 - were found to cause
hyperphosphorylation of tau, permanently dismantling the
microtubule bridges.
"This paper shows, for the first time, these three kinases affect
Alzheimer's disease-relevant tau hyperphosphorylation, in which
most of the tau protein is now driven into a permanently
phosphorylated form,'' Dr. Dunckley said.
Dr. Eric Reiman, clinical director of TGen's Neurogenomics Division
and executive director of the Banner Alzheimer's Institute,
explained that tau holds together the skeleton inside neurons. When
phosphate molecules stick to tau proteins, the skeleton falls apart
and the neurons begin to retract their synaptic branches and die,
leading to memory loss and thinking problems.
In this study, researchers used a molecular tool called siRNA to
screen the entire human genome, said Dr. Reiman, a co-author of the
scientific paper. This tool enabled the TGen-led team to discover
which proteins, when genetically turned off, prevent phosphate
molecules from sticking to tau. The three kinases, or proteins,
that appear to contribute to the formation of brain tangles, can
now be targeted by protein-inhibitor drugs.
"This study used a powerful tool to discover three proteins that
may be involved in tangle formation. If safe and well-tolerated
tangle-busting medications can be developed, they offer great
promise in the treatment of Alzheimer's disease,'' said Dr. Reiman,
who also is Director of the Arizona Alzheimer's Consortium.
The next step will be to identify drug compounds that can negate
the effects of the three kinases linked to tau
hyperphosphorylation.
"The reason that we did this study was to identify therapeutic
targets for Alzheimer's disease, whereby we could modify the
progression of tau pathology,'' Dr. Dunckley said. "This was a
screen to identify what the relevant targets are. Now, we want to
match those targets to treatments.''
TGen's collaborators in the study included: the Department of
Neurology at the Mayo Clinic in Jacksonville, Fla.; the Center for
Alzheimer's Research at the Sun Health Institute in Sun City,
Ariz.; Banner Alzheimer's Institute in Phoenix, Ariz.; the
Department of Psychiatry at the University of Arizona; and the
Arizona Alzheimer's Consortium, a group of nine institutes that
cooperatively study Alzheimer's disease.
*
About TGen
The Translational Genomics Research Institute (TGen) is a Phoenix,
Arizona-based non-profit organization dedicated to conducting
groundbreaking research with life changing results. Research at
TGen is focused on helping patients with diseases such as cancer,
neurological disorders and diabetes. TGen is on the cutting edge of
translational research where investigators are able to unravel the
genetic components of common and complex diseases. Working with
collaborators in the scientific and medical communities, TGen
believes it can make a substantial contribution to the efficiency
and effectiveness of the translational process. TGen is affiliated
with the Van Andel Research Institute in Grand Rapids, Michigan.
For more information, visit: www.tgen.org.
Press Contact:
Steve Yozwiak
TGen Senior Science Writer
602-343-8704
[email protected]
*
About the Arizona Alzheimer's Consortium
The Arizona Alzheimer's Consortium (AAC) is the nation's leading
model of statewide collaboration in Alzheimer's disease research.
Established in 1998, the Consortium capitalizes on its
participating institutions' complementary strengths in brain
imaging computer science, genomics, the basic and cognitive
neurosciences and clinical and neuropathology research to promote
the scientific understanding and early detection of Alzheimer's
disease and find effective disease-stopping and prevention
therapies. It also seeks to educate Arizona residents about
Alzheimer's disease, research progress in the state and the
resources needed to help patients, families and professionals
manage the disease. The Consortium is determined to find effective
treatments to halt the progression and prevent the onset of
Alzheimer's disease in the next 12 years. The Arizona Alzheimer's
Consortium is a 501(c)(3) organization that includes the
state-supported Arizona Alzheimer's Research Center (AARC), the
National Institute on Aging (NIA)-funded Arizona Disease Core
Center (Arizona ADCC), and independently funded research programs.
Its seven member institutions include: Arizona State University,
the Barrow Neurological Institute, the Mayo Clinic Arizona, the Sun
Health Research Institute, the Translational Genomics Research
Institute (TGen), the University of Arizona, and the recently
established Banner Alzheimer's Institute. Its three affiliated
institutions include Banner Good Samaritan Medical Center, the
Southern Arizona Veterans Administration Health Care System and the
University Physician's Hospital at Kino.
# # #