[GRG] Decreasing STEP levels reversed Alzheimer’s disease in mice

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Contact: PLOS Biology
biologypress@plos.org
PLOS

In search for Alzheimer’s drug, a major STEP forward

Researchers at Yale School of Medicine have discovered a new drug
compound that may help reverse the cognitive deficits of
Alzheimer’s disease. Their findings are publishing on August 5 in
the open access journal PLOS Biology.

The compound, TC-2153, inhibits the negative effects of a protein
called STriatal-Enriched tyrosine Phosphatase (STEP), which is key
to regulating learning and memory. These cognitive functions are
impaired in Alzheimer’s.

“Decreasing STEP levels reversed the effects of Alzheimer’s disease
in mice,” said lead author Paul Lombroso, M.D., professor in the
Yale Child Study Center and in the Departments of Neurobiology and
Psychiatry at Yale School of Medicine.

Lombroso and co-authors studied thousands of small molecules,
searching for those that would inhibit STEP activity. Once
identified, those STEP-inhibiting compounds were tested in brain
cells to examine how effectively they could halt the effects of
STEP. They examined the most promising compound in a mouse model of
Alzheimer’s disease, and found a reversal of deficits in several
cognitive exercises that gauged the animals’ ability to remember
previously seen objects.

High levels of STEP proteins keep synapses in the brain from
strengthening. Synaptic strengthening is a process that is required
for people to turn short-term memories into long-term memories.
When STEP is elevated in the brain, it depletes receptors from
synaptic sites, and inactivates other proteins that are necessary
for proper cognitive function. This disruption can result in
Alzheimer’s disease or a number of neuropsychiatric and
neurodegenerative disorders, all marked by cognitive deficits.

“The small molecule inhibitor is the result of a five-year
collaborative effort to search for STEP inhibitors,” said Lombroso.
“A single dose of the drug results in improved cognitive function
in mice. Animals treated with TC compound were indistinguishable
from a control group in several cognitive tasks.”

The team is currently testing the TC compound in other animals with
cognitive defects, including rats and non-human primates. “These
studies will determine whether the compound can improve cognitive
deficits in other animal models,” said Lombroso. “Successful
results will bring us a step closer to testing a drug that improves
cognition in humans.”

###

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1923

Contact:

Karen N. Peart
Senior Communications Officer
Yale School of Medicine
203-432-1326 or karen.peart@yale.edu

Citation: Xu J, Chatterjee M, Baguley TD, Brouillette J, Kurup P,
et al. (2014) Inhibitor of the Tyrosine Phosphatase STEP Reverses
Cognitive Deficits in a Mouse Model of Alzheimer’s Disease. PLoS
Biol 12(8): e1001923. doi:10.1371/journal.pbio.1001923

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About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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