Drug that enhances removal of toxic brain proteins
improves cognition in mice
Newswise, December 29, 2015--A drug that boosts activity in
the brain’s “garbage disposal” system can decrease levels of toxic proteins
associated with Alzheimer’s disease and other neurodegenerative disorders and
improve cognition in mice, a new study by neuroscientists at Columbia
University Medical Center (CUMC) has found.
The study was published today in
the online edition of Nature Medicine.
“We have shown for the first time that it’s possible to use a
drug to activate this disposal system in neurons and effectively slow down
disease,” said study leader Karen E. Duff, PhD, professor of pathology and cell
biology (in psychiatry and in the Taub Institute for Research on Alzheimer’s
Disease and the Aging Brain) at CUMC and at the New York State Psychiatric
Institute.
“This has the potential to open up new avenues of treatment for
Alzheimer’s and many other neurodegenerative diseases.”
The drug used was
rolipram, which causes nausea and thus is not a good drug for use in humans,
but similar drugs do not incur nausea as a side effect and could go into
clinical trials very quickly.
To remain healthy, brain cells must continually clear out old,
worn, or damaged proteins, a task performed by a small molecular cylinder
called the proteasome.
The proteasome acts as a kind of garbage disposal,
grinding up the old proteins so they can be recycled into new ones. In
neurodegenerative diseases, proteins tagged for destruction accumulate in the
brain’s neurons, suggesting that the cell’s proteasomes are impaired.
Using a mouse model of neurodegeneration, the researchers
first discovered that tau--a toxic protein that accumulates in Alzheimer’s and
other brain degenerative diseases--sticks to the proteasome and slows down the
protein disposal process.
Administering rolipram activated the proteasome and restored
protein disposal to normal levels. The drug also improved the memory of
diseased mice to levels seen in healthy mice.
Rolipram has been tested before in mice and was shown to
improve memory, but the mechanism for how this occurred was unclear. The new
research shows that by inhibiting of the PDE-4 enzyme, rolipram produces a
physical change in the proteasome that increases its activity.
“We still don’t know exactly where the activation is
happening, but what’s new is that we can modify the proteasome to increase its
activity. There could be many other ways to do this,” said the study’s first
author, Natura Myeku, PhD, an associate research scientist in pathology and
cell biology at CUMC.
Drugs that target proteasomes in this way should work for any
disease caused by the accumulation of abnormal proteins, including Alzheimer’s,
Huntington’s, Parkinson’s and frontotemperoral dementia.
“Treatments that speed up these cell disposal mechanisms
should, in theory, only degrade abnormal proteins. We don’t need to know what
the toxic form of the protein is,” Dr Duff said.
“In Alzheimer’s disease, there
are at least four different types: amyloid, tau, alpha-synuclein, and TDP43. A
well-functioning proteasome can clear out everything at once.”
“This exciting research from Dr. Duff’s team advances our
basic understanding of the proteasome system, provides a way to repair the
system when it breaks, and alleviates symptoms of neurodegenerative disorders,”
said Rod Corriveau, PhD, program director at the National Institute of Health’s
National Institute of Neurological Disorders and Stroke, which provided funding
for the study.
The study is titled, “26S proteasome dysfunction and cognitive
impairment caused by aggregated tau accumulation can be attenuated by
PKA-mediated phosphorylation of proteasomes.”
The other contributors are:
Catherine L. Clelland (CUMC), Sheina Emrani (CUMC), Nikolay V. Kukushkin (Harvard
Medical School, Boston, MA), Li Liu (CUMC), Yvette H. Figueroa (CUMC), and Wai
Haung Yu (CUMC).
The study was supported by grants from the National Institute
of Neurological Disorders and Stroke (NS074593), the CurePSP Foundation, the
National Institute of General Medical Sciences (GM051923), the Fidelity
Biosciences Research Initiative, and the Multiple Myeloma Research Foundation.
The researchers declare no financial or other conflicts of
interest.
The Taub Institute for Research on Alzheimer’s Disease and the
Aging Brain at Columbia University Medical Center is a multidisciplinary
group that has forged links between researchers and clinicians to uncover the
causes of Alzheimer’s, Parkinson’s, and other age-related brain diseases and to
discover ways to prevent and cure these diseases.
It has partnered with the
Gertrude H. Sergievsky Center at Columbia University Medical Center, which was
established by an endowment in 1977 to focus on diseases of the nervous system,
and with the Departments of Pathology & Cell Biology and of Neurology to
allow the seamless integration of genetic analysis, molecular and cellular
studies, and clinical investigation to explore all phases of diseases of the
nervous system. For more information, visit The Taub Institute at www.cumc.columbia.edu/dept/taub/.
The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast.
For more information, visit www.cumc.columbia.edu or www.columbiadoctors.org
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