Re: [GRG] NewAbs: Rx: Fisetin Used for Mouse Model of AD

Here is its structure and chemical-biological information on fisetin. Note the polyphenol structure like resveratrol.

Elliot

http://ift.tt/1fp1xa6

On Jan 31, 2014, at 12:01 AM, L. Stephen Coles, M.D., Ph.D. wrote:

Vint: Is Ray keeping you up-to-date on AD? Else let me know.
— Steve Coles

“Natural Plant Compound Prevents
Alzheimer’s Disease in Mice”

Fisetin reduces
(Right) astrocytic reactivity in the brains of Alzheimer’s Disease mice.
Scale bar: 10 microns.
(Credit: Antonio Currais et al./Aging Cell)
January 30, 2014; (Kurzweil AI) — A daily dose of
fisetin, an  antioxidant chemical that’s found in
fruits and vegetables from strawberries to cucumbers, appears to stop
memory loss that accompanies
Alzheimer’s
disease in mice, scientists at the
Salk Institute for Biological Studies
have discovered.In
experiments on mice that normally develop Alzheimer’s symptoms less than
a year after birth, a daily dose of the compound prevented the
progressive memory and learning impairments.The drug,
however, did not alter the formation of amyloid plaques in the brain,
accumulations of proteins that are commonly blamed for Alzheimer’s
disease. The new finding suggests a way to treat Alzheimer’s symptoms
independently of targeting amyloid plaques.“We had
already shown that in normal animals, fisetin can improve memory,†says
Pamela Maher, a senior staff scientist in Salk’s

Cellular Neurobiology Laboratory who led the new study. “What we
showed here is that it also can have an effect on animals prone to
Alzheimer’s.â€More than
a decade ago, Maher discovered that fisetin helps protect neurons in the
brain from the effects of aging. She and her colleagues have since ­- in
both isolated cell cultures and mouse studies ­- probed how the compound
has both antioxidant and anti-inflammatory effects on cells in the brain.
Most recently, they found that fisetin turns on a cellular pathway known
to be involved in memory.“What we
realized is that fisetin has a number of properties that we thought might
be beneficial when it comes to Alzheimer’s,†says Maher.
The fisetin protective mode of action
(Credit: Antonio Currais et al./Aging Cell)The ExperimentsSo Maher ­
who works with Dave
Schubert, the head of the Cellular Neurobiology Lab ­- turned to a
strain of mice that have mutations in two genes linked to Alzheimer’s
Disease. The researchers took a subset of these mice and, when they were
only three months old, began adding fisetin to their food.As the
mice aged, the researchers tested their memory and learning skills with
water mazes. By nine months of age, mice that hadn’t received fisetin
began performing more poorly in the mazes. Mice that had gotten a daily
dose of the compound, however, performed as well as normal mice, at both
nine months and a year old.  “Even as the disease would have been
progressing, the fisetin was able to continue preventing symptoms,†Maher
says.In
collaboration with scientists at the
University of California, San Diego,
Maher’s team next tested the levels of different molecules in the brains
of mice that had received doses of fisetin and those that hadn’t. In mice
with Alzheimer’s symptoms, they found, pathways involved in cellular
inflammation were turned on. In the animals that had taken fisetin, those
pathways were dampened and anti-inflammatory molecules were present
instead.One
protein in particular ­ known as p35 ­ was blocked from
being cleaved into a shorter version when fisetin was taken. The
shortened version of p35 is known to turn on and off many other molecular
pathways. The results were published December 17, 2013, in the journal
Aging Cell.Next stepsNext,
Maher’s team hopes to understand more of the molecular details on how
fisetin affects memory, including whether there are targets other than
p35. “It may be that compounds like this that have more than one target
are most effective at treating Alzheimer’s Disease,†says Maher, “because
it’s a complex disease where there are a lot of things going
wrong.† They also aim to develop new studies to look at how the
timing of fisetin doses affect its influence on Alzheimer’s.“The model
that we used here was a preventive model,†explains Maher. “We started
the mice on the drugs before they had any memory loss. But obviously
human patients don’t go to the doctor until they are already having
memory problems.†So the next step in moving the discovery toward the
clinic, she says, is to test whether fisetin can reverse declines in
memory once they have already appeared.
__________________________
The work was supported by grants from the Alzheimer’s Association, Paul
Slavik, the National Institutes of Health, the Alzheimer’s Drug Discovery
Foundation, and the George E. Hewitt Foundation.

Abstract of Aging Cell paper:
Alzheimer’s Disease (AD) is the most common type of dementia. It is the
only one of the top ten causes of death in the USA for which prevention
strategies have not been developed. Although AD has traditionally been
associated with the deposition of amyloid plaques and tau
tangles, it is becoming increasingly clear that it involves
disruptions in multiple cellular systems. Therefore, it is unlikely that
hitting a single target will result in significant benefits to patients
with AD. An alternative approach is to identify molecules that have
multiple biological activities that are relevant to the disease.
Fisetin is a small, orally active molecule which can act on many of
the target pathways implicated in AD. We show here that oral
administration of fisetin to APPswe/PS1dE9 double transgenic AD mice from
[3 to 12] months of age prevents the development of learning and memory
deficits. This correlates with an increase in ERK phosphorylation along
with a decrease in protein carbonylation, a marker of oxidative stress.
Importantly, fisetin also reduces the levels of the Cyclin-dependent
kinase 5 (Cdk5) activator p35 cleavage product, p25, in both control and
AD brains. Elevated levels of p25 relative to p35 cause dysregulation of
Cdk5 activity leading to neuroinflammation and neurodegeneration. These
fisetin-dependent changes correlate with additional anti-inflammatory
effects, including alterations in global eicosanoid synthesis, and the
maintenance of markers of synaptic function in the AD mice. Together,
these results suggest that fisetin may provide a new approach to the
treatment of AD.
Refs.:

Antonio Currais et
al., Modulation of p25 and inflammatory pathways by fisetin maintains
cognitive function in Alzheimer’s disease transgenic mice, Aging
Cell, 2013, DOI:
10.1111/acel.12185

Related:

Natural plant compound prevents Alzheimer’s disease in
mice
Topics: Cognitive Science/Neuroscience

At 10:04 AM 1/30/2014, you wrote:
Steve: This was in KurzweilAI
this morning… — Phil Kernan
http://ift.tt/1khIpwy

L. Stephen Coles, M.D., Ph.D., Co-Founder
Los Angeles Gerontology Research GroupURL:
http://www.grg.org
E-mail: scoles@grg.orgE-mail:
scoles@ucla.edu

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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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