Nobel Winner Paul Greengard, 84, Identifies Potential Key To Halting Alzheimer’s.
September 2, 2010
Scientist Paul Greengard first became interested in Alzheimer’s twenty-five years ago when his father-in-law developed the disease. Now, the 84-year-old researcher, awarded a Noble Prize in 2000 for his work on how brain cells communicate, may have found a target for drugs that could slow or stop the progress of the now untreatable disease.
Greengard, who still works seven days a week in his Rockefeller University laboratory in New York City, recently identified a new protein that is key to the development of beta amyloid, the destructive plaque that builds up in the brains of people with Alzheimer’s and is a hallmark of the disorder, according to a study published today in Nature.
“This really is a new approach,” said Dr. Paul Aisen, of the University of California, San Diego, told Gina Kolata of The New York Times. “The work is very strong, and it is very convincing.” Dr. Aisen directs a program financed by the National Institute on Aging to conduct clinical trials of treatments for Alzheimer’s disease.
In Greengard’s lab, when scientists knocked out a gene that produces the new protein, called γ-secretase activating protein (GSAP), mice used in the experiment developed fewer amyloid plaques. GSAP works through a mechanism involving its interactions with γ-secretase, an enzyme that chops up the amyloid precursor protein, a large molecule produced naturally in the body and found in many different types of cells.
“Alzheimer’s disease is a devastating disorder for which there are no satisfactory treatments,” says Greengard, Vincent Astor Professor and director of the Fisher Center for Alzheimer’s Research at Rockefeller. “Our findings reveal that γ-secretase activating protein is a potential target for a new class of anti-amyloid therapies.”
While the discovery is exciting researchers recently deflated by setbacks in the research of anti-Alzheimer’s drugs, that the finding comes out of his lab will surprise few who know Greengard, who walks to work each day with his Bermese mountain dog, Alpha.
Born in New York City in 1925, Greengard’s Jewish mother, Pearl Meister, died in childbirth. After his father’s remarriage, Greengard was raised as an Episcopalian and denied awareness of his mother’ family or his Jewish heritage, which he discovered later in life.
He used his Nobel Prize money to create the Pearl Meister Greengard Prize, to honor women scientists and combat discrimination against women in science. Self-depricating, at the time he announced the prize, he said before the Nobel Prize his greatest previous prize came from winning a Boy Scout potato sack race.
During World War II, he served in the United States Navy as an electronics technician at the Massachusetts Institute of Technology working on an early warning system against Japanese kamikaze planes. He graduated from Hamilton College in 1948 with a bachelor’s degree in mathematics and physics, but chose to pursue biophysics in graduate school because post-war physics research was focusing on nuclear weapons.
While studying for his Ph.D. at Johns Hopkins University, a lecture by Alan Hodgkin, a Nobel Prize winner in 1963, inspired him to begin work on the molecular and cellular function of neurons.
Until now, scientists have been searching for ways to reduce amyloid-β production in Alzheimer’s patients by blocking γ-secretase, but most γ-secretase inhibitors also block the cleavage of an important immune system molecule called Notch. Notch plays a pivotal role in the development of blood-forming organs and the immune system. Earlier research by Greengard and his colleagues showed that Gleevec, a drug used to treat leukemia and gastrointestinal stromal tumors, successfully inhibited the ability of γ-secretase to form amyloid-β without affecting the Notch pathway.
In the new study, led by Gen He, a research associate in Greengard’s lab, the researchers showed that GSAP stimulates production of amyloid-β in cell lines, and that reducing GSAP reduces amyloid-β.
Unfortunately, the Gleevec molecule does not cross the blood-brain barrier, the gatekeeper that prevents some substances in the blood from entering the brain. Greengard, however, believes that it will be possible to design drugs that target GSAP but do not have this limitation.
“Anti-amyloid therapeutic drugs represent a valid approach to treating Alzheimer’s disease, but their inability to accumulate in the brain has limited their usefulness,” says Greengard, who is head of the Laboratory of Molecular and Cellular Neuroscience. “The development of compounds that work like Gleevec, but have the ability to pass the blood-brain barrier and target GSAP, could revolutionize the treatment of this disease.”
Why Dance? To Maintain Everyday Competence And Stay Fit Physically And Mentally, Study Shows
August 10, 2010
Why dance?
Beyond the joy of bopping to rhythm and staying in shape, a growing tide of research has been pointing to dance’s ability to preserve mental fitness, too.
Now, a new study suggests that following a regular schedule of dancing into old age has far-reaching effects that not only preserve cognitive, motor, and perceptual abilities, but is “a prime candidate for the preservation of everyday life competence of elderly individuals.”
In recent years, dance has been used as a therapeutic tool for the treatment of Parkinson’s disease, dementia, obesity in children, and patients with serious mental illness. Most previous studies have focused on its benefit to the cardiovascular health, muscle strengthening, posture, and balance among the elderly.
Using PET scans, neuroscientists have previously shown that dancing activates many areas of the brain and elicits the interaction of wide-spread neural networks. Other studies have shown that repeated physical activities have the ability to reorganize the brain, otherwise known as neuroplasticity, into old age.
“We here went one step further by hypothesizing that year-long dancing activity in an elderly population should promote general advantages including preservation of cognitive, motor and sensorimotor performance as well as perceptual abilities,” according to the study by researchers, led by Jan-Christoph Kattenstroth, at the Neural Plasticity Lab at the Institute for Neuroinformatics, Ruhr-University Bochum.
They studied the impact on 24 amateur dancers, with an average age of 71 and an average of 16.5 years of regular ballroom dancing, compared with a sedentary group of 38 adults, of the same average age, with no record of sports or dancing activities.
“We found that in each of the different levels investigated,” including cognitive, attentional, intellectual, perceptual and sensorimotor performance, the group of amateur dancers performed at a superior level compared with the group of non-dancers.
The advantages of dance, in addition to physical activity, may result from its unique combination of other elements, including engagement of emotions, social interaction, sensory stimulation, motor coordination and music.
Interestingly, in a recent study, experienced adult Tai Chi practitioners demonstrated superior spatial sense and sensitivity of touch, in comparison to matched control subjects. As one explanation, researchers in that study proposed that either individuals with a high fitness are drawn to Tai Chi, or that Tai Chi itself drives cortical changes which lead to superior tactile acuity.
But researchers at the Neural Plasticity Lab suggested that increased levels of neurotrophins, “up-regulated,” or produced, during dancing might also be responsible for the superior tactile acuity seen in Tai Chi practicioners. Neurotrophins are a family of proteins, or growth factors, capable of signaling which neurons, or brain cells, survive, differentiate, or grow.
The group of amateur dancers in the lab’s study scored higher than the passive group in everyday competence, as measured by a everyday competence questionnaire. It looked at various aspects of independent living and mobility, social relations, general health, and contentment.
“Our study provides strong evidence that dance promotes a wide-range of beneficial effects,” the study concluded. “Therefore, dance might be an approach” to maintaining brain health and plasticity and contribute to successful aging.
Rx For Learning And The Brain: Music; The Duke of Uke Demonstrates & Nina Kraus Explains
July 23, 2010
Nothing attests to the hunger for music more than the ubiquitous sight of thin white wires draped like jewelry from ears and plugged into devices, playing who knows what: Bach? Beyonce? Bieber?
Noticing the other day how many riders on the subway were wired up, I mused that it was no wonder Dr. Rudolfo Llinás, a giant of modern neuroscience, speaks of the the life of cells in the brain as looking “like a Riverdance perfomance,” with “some cells tapping in harmony and some … silent, creating myriads of patterns that represent the properties of the external world. Cells with the same rhythm form circuits to bind information in time.”
Nor does it surprise that an explosion of studies in recent years has suggested that music on the brain is a good thing, good for learning and longevity. Consider this disparate group of musicians and their current ages: BB King, 84; Earl Scrugg, 86, Ravi Shankar, 90, ‘Honeyboy’ Edwards, 95; and Pinetop Perkins, 96; or the world’s oldest performing musician, Bill Tapia, the Duke of the Uke, 102, who appeared recently at the New York Uke Festival.
Now a data-driven review has pulled together studies linking musical training to learning, from skills ranging from language to memory. And scientists who published their work this week in Nature Reviews Neuroscience say that collectively the research has significant implications for education.
Playing an instrument, the researchers say, primes the brain to choose what is relevant in a complex process that may involve reading or remembering a score, timing issues and coordination with other musicians.
“The brain is unable to process all of the available sensory information from second to second, and thus must selectively enhance what is relevant,” Nina Kraus, lead author of the Nature perspective, the Hugh Knowles Professor of Communication Sciences and Neurobiology and director of Northwestern’s Auditory Neuroscience Laboratory.
“A musician’s brain selectively enhances information-bearing elements in sound,” Kraus said. “In a beautiful interrelationship between sensory and cognitive processes, the nervous system makes associations between complex sounds and what they mean.” The efficient sound-to-meaning connections are important not only for music but for other aspects of communication, she said.
Musicians are more successful than non-musicians in learning to incorporate sound patterns for a new language into words, according to literature gathered in the Nature review. Children who are musically trained show stronger neural activation to pitch changes in speech and have a better vocabulary and reading ability than children who did not receive music training.
And musicians trained to hear sounds embedded in a rich network of melodies and harmonies are primed to understand speech in a noisy background. They exhibit both enhanced cognitive and sensory abilities that give them a distinct advantage for processing speech in challenging listening environments compared with non-musicians.
Children with learning disorders are particularly vulnerable to the deleterious effects of background noise, according to the article. “Music training seems to strengthen the same neural processes that often are deficient in individuals with developmental dyslexia or who have difficulty hearing speech in noise.”
Their review, Northwestern researchers conclude, argues for serious investing of resources in music training in schools accompanied with rigorous examinations of the effects of such instruction on listening, learning, memory, attention and literacy skills.
(Part of this post was adapted from materials provided by by Northwestern University.)
Cell Rest and Teen Exercise Are Keys To Later Brain Health
July 1, 2010
It can’t be said too often: to protect your brain, exercise! Now, two new studies are adding more emphasis to physical activity— and greater understanding to the interplay between exercise, aging and the exquisite balance that preserves the brain’s reservoir of stem cells for later life.
One study focused on the cellular mechanism that keeps neural stem cell division in check. The other correlated the lack of teenage exercise with cognitive impairment in later life.
In the first, scientists at the Salk Institute of Biological Research in La Jolla, California, underscored how physical activity balances neural stem cell quiescence— stem cells are at rest— and keep them from their dormancy from becoming dominant in later life while it helps stimulate the growth of new neurons in the hippocampus, the brain’s hub of memory.
Image: Courtesy of Dr. Helena Mira, Carlos III Health Institute, Madrid
The other study, of 9,344 women from Maryland, Minnesota, Oregon, and Pennsylvania, compared at activity levels at teenage, age 30, age 50, and late life with cognitive decline. Reported June 30 in the Journal of the American Geriatrics Society, it held alarming implications in an era of declining physical activity for youths.
“Our study shows that women who are regularly physically active at any age have lower risk of cognitive impairment than those who are inactive,” said lead researcher Laura Middletton, Ph. D., of Sunnybrook Health Sciences Center in Toronto. “But … being physically active at teenage is most important in preventing cognitive impairment.”
Researchers, led by Laura Middleton, Ph. D., of Sunnybrook Health Sciences Centre, found that being physically active at any stage of life lowers the risk of cognitive impairment in old age. But “being physically active at teenage is most important in preventing cognitive impairment,” said lead researcher Laura Middleton, Ph. D., of Sunnybrook Health Sciences Centre, Canada.
The researchers also determined that women who were physically inactive at teenage but became physically active at age 30 and age 50 had significantly reduced odds of cognitive impairment relative to those who remained physically inactive. In contrast, being physically active at age 30 and age 50 was not significantly associated with rates of cognitive impairment in those women who were already physically active at teenage.
“To minimize the risk of dementia, physical activity should be encouraged from early life,” Middleton said, adding, “Not to be without hope, people who were inactive at teenage can reduce their risk of cognitive impairment by becoming active in later life.”
The mechanisms by which cognition benefits from physical activity across the life course are believed multi-factorial. Much evidence already suggests that physical activity positively effects brain plasticity and cognition and that physical activity reduces the rates and severity of vascular risk factors, such as hypertension, obesity, and type II diabetes associated with increased risk of cognitive impairment.
“Low physical activity levels in today’s youth may mean increased dementia rates in the future. Dementia prevention programs and other health promotion programs encouraging physical activity should target people starting at very young ages, not just in mid- and late life,” said Middleton.
Some of the cognitive issues of aging may be the result of an unchallenged process by which stem cells in the brain remain dormant until called upon to produce more neurons, ensuring a pool of neurons that lasts a lifetime.
In research published in the July 1 issue of Cell Stem Cell, researchers identified the importance of bone morphogenetic factor protein (BMP) in preventing the rampant proliferation and depletion of neural stem cells.
Using prior observation that quiescent neural stem cells express the BMP receptor 1A as a starting point, co-first author Helena Mira, formerly a post-doc in senior author Fred H. Gage’s Laboratory for Genetics at the Salk Institute and now an assistant professor in the Department of Cell Biology and Development at the Carlos III Health Institute in Madrid, and her collaborators investigated the role of BMP signaling in regulating the proliferation of stem cells located in the hippocampus, one of two brain regions harboring neural stem cells.
They found that BMP signaling, which is triggered by the interaction of BMPs with their receptors, is inactive in most proliferating cells, whereas it is active in non-dividing cells, including quiescent stem cells and differentiated neurons. Unlike stem cells, mature neurons express BMP receptor 1B, which will be the focus of future studies.
Experiments with cultured neural stem cells confirmed that it was indeed BMP that kept them quiet. BMP’s anti-proliferative effect was blocked when BMP was replaced with a protein known as Noggin, which binds and inactivates members of the BMP family.
The researchers observed the same effect when they delivered Noggin directly into the brains of adult mice. Here, too, Noggin successfully interfered with BMP signaling and raised quiescent stem cells out of their slumber. After one week, those neural stem cells had started dividing and their offspring were well on their way to becoming neurons.
When neural stem cells were forced to proliferate over prolonged periods of time, however, the pool of active neural stem cells was depleted, suggesting to Gage and his team that quiescence functions as a protective mechanism that counteracts stem cell exhaustion.
“It tells you how finely this process is regulated,” says Mira. “BMP ensures a sufficiently big population of quiescent stem cells that can feed into the system when called upon.”
Gage, the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases, will next investigate whether BMP is the linchpin that links exercise, aging and neurogenesis. “As we age, the number of new neurons declines but physical exercise brings that number back up,” he said. “Our findings raise the possibility that the BMP signal becomes dominant over time, forcing neural stem cells deeper into quiescence and thus making it harder to generate new brain cells.”
This post was based on reports at the Salk Insitute website, at http://www.salk.edu/news/pressrelease_details.php?press_id=428
Poet Joe Enzweiler and His Cabin Door in Alaska
May 8, 2010
There are days I truly love the Internet. This morning was one of them. Searching for news from the frontiers of neuroscience, I found Joseph Enzweiler. He is a physicist-turned-poet and stone mason who remade his life in rural Alaska, rejecting a life defined by a career in favor of one defined by his attention to life.
“Time—not cash—is the treasure in life,” he recently told the alumni magazine of Xavier University. “That’s what I wanted. I understood the bargain: I gave up a career-type job so I could write poetry and live a life more in keeping with the cycles of the seasons. I’m off the grid, no plumbing, no mortgage, no bills. It’s not for everybody, but this way of life has suited me.” In a story posted on the website of the Cinncinnati Brain Tumor Center, the author of five books of poetry added his rationale: “I want my silence.”
During the summer of 2009, Joe was diagnosed and later treated for a brain tumor in his native Ohio. I’ll post the links to the excellent stories in Xavier Alumni magazine and on CBTC site below, but first I’m hoping you’ll read Joe’s poem “Cabin Door,” from his collection A Winter on Earth, published by Iris Books, and listen to him reading it during an interview with Barbara Gray @ wxvu 91.7 radio in Cinncinnati.
It is a poem of considerable beauty and depth and humanity, built with the kind of word-by-word craft with which, easy to imagine, Joe also builds his walls. I love that I can see and feel the door at the same time I can feel it opening a portal in my own brain through which I enter Joe’s life, hearing the voice of his father come back to him in the voice of the door, the door through which he passes into the physical world and back into the world of mind and memory. Its closing line contains a wish I share with the readers of What Should I Do With The Rest Of My Life?
“Cabin Door”
Friend, mute thing
I shake hands with
every day, who for
twenty-five years
let me escape
in both directions,
I remember the night
of the Coleman lamps
when I was so young
the world was all
fiberglas and plywood,
my breath an apparition
in the block of cold
that would be home.
And you, too heavy
to lift, sledded here
by moonlight, shimmered
and bolted on, felt
around the edges to seal
out the rapier wind.
As if this was my
spaceship to the stars,
emissary in a corner chair
from a world that,
as I arrive in greeting
light years hence,
is no longer there.
You watched it all,
June’s leafy sun, winter
loosening into sap and mud.
On the other side,
old loves of mine
and meals alone.
Till I stand up
one more time, put on
my coat and greet you.
Daylight floods in hinged
and white. Don’t wait
for me. Can’t promise
I’ll be back, as you
repeat what my father
told me once, from your
deepening veneer:
“I hope you find
what you’re looking for.”
Radio interview with Barbara Gray at WVXU:WXVU interview with Joe Enzweiler
Here are the links to the story from the Xavier Magazne by Greg Shaber Xavier profile Enzweiler and the Cinncinnati Brain Tumor Center Cinncinnati Brain Tumor Center - Enzweiler .
The Cost of Commuting, Mood and Movement
April 2, 2010
The other day, New York Times columnist David Brooks, summarizing recent research into happiness, wrote that while “the relationship between money and well-being is complicated, the correspondence between personal relationships and happiness is not. The daily activities most associated with happiness are sex, socializing after work and having dinner with others. The daily activity most injurious to happiness is commuting.”
According to studies, joining a group and going to just one meeting a month produces happiness equivalent to doubling your income, while being married is equal to adding $100,000 to your annual earnings, Brooks writes.
In his blog, The Frontal Cortex, neuroscientist Jonah Lehrer delves more deeply into studies that suggest that when purchasing homes people regularly underestimate the pain of a longer commute in favor of the seduction of getting a larger house. “The commuters paradox,” as it was called by Swiss economists Bruno Frey and Alois Stutzer, found that this miscalculation leads people to mistakenly believe that the big house in the exurbs will make them happier, even though it might force them to drive an additional hour to work. Frey and Stutzer also found that a person with a one-hour commute has to earn 40 percent more money to be as satisfied with life as someone who walks to the office.
The reason commuting is so painful, says Lehrer, citing other research, is that traffic inherently unpredictable and therefore we can’t habituate ourselves to it. “Driving in traffic is a different kind of hell every day,” says Harvard psychologist Daniel Gilbert. Nonetheless, our commutes get ever longer, with more than 3.5 million Americans now spending more than three hours each day traveling to work and home. The reason why it has such a depressing effect on us, I would speculate is different: Sitting. Not moving our bodies, that is. Muscular inactivity.
A newly-released study by Indiana University researchers (and reported on the university website @ http://bit.ly/bJH0Y3) found that physical activity throughout the day—simply moving—is related to positive feelings.
“In the study, if people are more active, they tend to report a more positive mood,” said Bryan McCormick, associate professor in IU Bloomington’s School of Health, Physical Education and Recreation (HPER). “Really low levels of activity are related to lower levels of positive affect.”
Physical activity was considered any movement beyond resting, not formal exercise.
“People often see physical activity as having to be exercise, but it doesn’t have to be exercise,” McCormick said. “Physical activity beyond a resting state does appear to be related to mood.”
The Indiana study tracked moment-by-moment physical activity throughout the day and compared it to reports study participants made of their activities and feelings each day. The 25 study participants wore uniaxial accelerometers during waking hours for seven days so their physical activity could be recorded. They also wore wristwatches with pre-programmed alarms that signaled them seven times per day to remind them to fill out brief reports. If they responded more than 20 minutes after the alarm, their report was disregarded to eliminate the ambiguity of “recall.”
Add to this recent findings about a possible connection between long bouts of television watching and a shorter lifespan. In a paper, released earlier this year, the journal Circulation: Journal of the American Heart Association, found that every hour spent watching television was associated with an 18% greater risk of dying from cardiovascular disease, an 11% greater risk of all causes of death, and a 9% increased risk of death from cancer. The link between TV watching and death from cardiovascular disease existed not just among the overweight and obese, but also among people who exercised and were at at healthy weight.
Those findings prompted Swedish exercise experts from Karolinska Institute and the Swedish School of Sport and Health Sciences to write an editorial published in January online in the British Journal of Sports Medicine about establishing a new way of thinking about sedentary behavior. They suggest abolishing “sedentary behavior” as a synonym for not exercising. Instead, sedentary time should be defined as “muscular inactivity” to distinguish it from not doing any exercise at all.
Underlying their recommendation are four principles:
1. Just sitting and not moving throughout the day may in itself increase the risk of disease.
2. Sedentary behavior is a separate kind of behavior with its own effects on the risk of disease, and is different from leisure-time exercise.
3. The molecular and physiological changes that occur from sitting too much are sometimes different from the body’s response to a period of physical activity.
4. Those already too inactive are increasing their health risks further by sitting for long periods of time.
They suggest abolishing “sedentary behavior” as a synonym for not exercising. Instead, sedentary time should be defined as “muscular inactivity” to distinguish it from not doing any exercise at all. While they encourage people to continue regular exercise, they recommend increasing muscular activity throughout the day by taking a 5 minute break every hour from sedentary behavior. And while they urge people to continue regular exercise, they warn that the body can’t just be planted for the other 17 hours a day. More on the issue of mood and movement later. But first, I’ve got to get up and move!