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c-Abl Linked to Alzheimer's Disease

c-Abl Linked to Alzheimer's Disease\

Wednesday, May 25, 2011

c-Abl Linked to Alzheimer's Disease

After decades of studying the pathological process that wipes out large volumes of memory, scientists at The Feinstein Institute for Medical Research discovered a molecule called c-Abl that has a known role in leukemia also has a hand in Alzheimer's disease...

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After decades of studying the pathological process that wipes out large volumes of memory, scientists at The Feinstein Institute for Medical Research discovered a molecule called c-Abl that has a known role in leukemia also has a hand in Alzheimer's disease. The finding, reported in the June 14th issue of the Journal of Alzheimer's Disease, offers a new target for drug development that could stave off the pathological disease process.



New protein linked to Alzheimer's disease

Peter Davies, PhD, head of the Feinstein Institute's Litwin-Zucker Center for Research in Alzheimer's Disease, became interested in c-Abl when he found that the protein was part of the plaques and tangles that crowd the brains of Alzheimer's patients. The protein c-Abl is a tyrosine kinase involved in cell differentiation, cell division and cell adhesion. In patients with chronic myeloid leukemia (CML), c-Abl is turned up in B cells. Inhibiting c-Abl with the cancer drug Gleevec prevents cell division. There was quite a lot known about c-Abl when Dr. Davies began thinking about its possible role in Alzheimer's. He was looking at kinases that phosphorylate tau, the protein that accumulates inside of the neurons during the disease process.

Dr. Davies questioned whether activated c-Abl turned on the cell cycle and could kill adult cells. He designed the study to test this idea and found that turning on the cell cycle in adult brain damages the cells. In their current study, the investigators devised a clever way to activate c-Abl in neurons of normal adult mice. They turned on human c-Abl genes in two different regions – the hippocampus and the neocortex – in adult mice and discovered abundant cell death, especially in the hippocampus. "You don't even need to count, you can just look and see holes in the cell layers of the hippocampus," said Dr. Davies. "It is stunning. Even before the neurons die, there is florid inflammation."

He said that the animal model is ideal for testing the benefit of drugs that turn off c-Abl. While Gleevec works in CML, it does not cross the blood-brain barrier so it would not be useful. Dr. Davies and his colleagues are looking for other drugs that inhibit c-Abl and can get into the brain. "We have a great model to test compounds for Alzheimer's disease. Will regulating c-Abl make a difference for patients? We won't know unless we try it in double blind clinical trials."

The researchers are now working to understand the mechanism of cell death. They are also investigating why males die considerably sooner than females – 12 to 15 weeks compared to 24 to 26 weeks. "It is an incredibly interesting model," said Dr. Davies. "If c-Abl is important we can learn how it works."

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The paper detailing the findings has been published in an early online version. It is scheduled for publication in the June 14th issue of the Journal of Alzheimer's Disease (http://www.j-alz.com).

About The Feinstein Institute for Medical Research

Headquartered in Manhasset, NY, The Feinstein Institute for Medical Research is home to international scientific leaders in Parkinson's disease, Alzheimer's disease, psychiatric disorders, rheumatoid arthritis, lupus, sepsis, inflammatory bowel disease, diabetes, human genetics, leukemia, lymphoma, neuroimmunology, and medicinal chemistry. The Feinstein Institute, part of the North Shore-LIJ Health System, ranks in the top 6th percentile of all National Institutes of Health grants awarded to research centers. For more information: www.FeinsteinInstitute.org

A Heart-Healthy Diet That’s Good for the Brain...

 

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May 24, 2011 Nutrition scientists continue to extol the virtues of a Mediterranean diet, the traditional diet from Italy, Greece and other countries that border the Mediterranean Sea. The diet, high in fruits and vegetables and healthy fats like olive oil, along with modest amounts of red wine and little red meat, may curb heart disease and prolong life – and keep your mind sharp and free of Alzheimer’s disease in old age, studies suggest.
Now a large new study from Rush Medical College in Chicago provides the strongest evidence to date that a Mediterranean style diet may be good for the brain. Researchers studied 3,790 men and women ages 65 and older, tracking them over many years beginning in 1993. They were given regular questionnaires about the foods they ate, along with tests of memory and thinking skills every three years.
Those seniors who adhered to a Mediterranean diet most strictly scored higher on mental acuity and memory tests than those who didn’t eat much of the heart-healthy foods. Overall, those who stuck most closely to a Mediterranean diet were two years younger in “brain age” than their peers who didn’t follow such a diet. The findings held even after adjusting for risk factors like age, sex, race, years of education and participation in mentally stimulating activities.
The researchers caution that they could not account for all the many factors that may contribute to cognitive decline in old age. Food surveys, in which people fill out what they eat, can be unreliable, though the researchers used scientifically validated methods to analyze the results, and the study involved a large number of people.
The findings, which appeared in the American Journal of Clinical Nutrition, bolster a growing body of evidence that a heart-healthy Mediterranean diet is good for the brain. Earlier, smaller studies have reported that healthy people who follow a Mediterranean diet lower their risk of developing Alzheimer’s disease. And those with Alzheimer’s who followed such a diet lived longer than their peers who did not. Earlier research has also shown that a Mediterranean diet may cut the risk of strokes, cancer, diabetes and possibly other illnesses as well.
Doctors are not sure why a Mediterranean diet may be good for the brain. One possibility is that such a diet reduces a risk for blood vessel disease, which may contribute to the risk for Alzheimer’s disease. A Mediterranean diet helps cut down on inflammatory substances in the body, too, and inflammation has increasingly been tied to heart disease and possibly Alzheimer’s as well. Fruits, vegetables and red wine are also high in cell-protecting antioxidants.
Key components of the Mediterranean diet include:

• An abundance of fiber-rich fruits, vegetables, cereals, nuts and beans;
• Choosing “good” fats like olive or canola oil, rather than butter or lard, and limiting dairy products like high-fat cheese and milk;
• Eating moderate amounts of fish and poultry, rather than red meat; and
• Drinking a glass or two of red wine a day.

Many other factors besides diet, including the genes you inherit and advancing age, play an important role in who ultimately develops Alzheimer’s. Still, the findings suggest that lifestyle factors can have an impact on Alzheimer’s risk. Eating a heart-healthy diet, along with getting regular exercise and keeping weight down, may help keep the brain young.
By ALZinfo.org, The Alzheimer’s Information Site. Reviewed by William J. Netzer, Ph.D., Fisher Center for Alzheimer’s Research Foundation at The Rockefeller University.
Source: Tangney CC, Kwasny MJ, Li H, Wilson RS, Evans DA, Morris MC: “Adherence to a Mediterranean-type dietary pattern and cognitive decline in a community population.” American Journal of Clinical Nutrition, Dec. 22, 2010.

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May 24, 2011

Having a thick middle, high blood pressure and other risk factors for heart disease may increase your risk of Alzheimer’s disease and other forms of dementia as well, a new study reports.

The findings come from France, where researchers studied more than 7,000 men and women ages 65 and older living in three French cities. Those who had a constellation of symptoms called “metabolic syndrome” – including hypertension, a large waistline, high levels of a type of blood fat called triglycerides, low levels of “good” HDL cholesterol, and poor control of blood sugar, a sign of impending diabetes – tended to perform worse on memory and thinking skills tests than those without these issues. Performing poorly on such tests is often an indicator of an increased risk of Alzheimer’s and other forms of dementia. The findings appeared in Neurology, the medical journal of the American Academy of Neurology.

Metabolic syndrome has long been linked to an increased risk of heart attacks. It is not an actual disease but rather a group of symptoms. The findings support a growing body of evidence that factors like a large waistline and high blood pressure – whether in midlife or beyond — may be linked to diminishing thinking skills and possibly even Alzheimer’s disease.

“Our study sheds new light on how metabolic syndrome and the individual factors of the disease may affect cognitive health,” said study author Christelle Raffaitin, M.D., of the French National Institute of Health Research in Bordeaux. “Our results suggest that management of metabolic syndrome may help slow down age-related memory loss, or delay the onset of dementia.”

At the start of the study, researchers evaluated the 4,323 women and 2,764 men and found that 16 percent had metabolic syndrome. All the participants were given memory tests two and four years later.

Those with metabolic syndrome were 20 percent more likely to have a decline in thinking and memory skills than those without the syndrome. Two factors in particular were linked to declining memory: higher triglycerides and low HDL, or “good” cholesterol. Having diabetes was also linked to memory problems, although high blood sugar levels were not.

The authors propose that taking steps to reduce metabolic syndrome may help to ward off or slow down mental decline in old age. Increasingly, Alzheimer’s is seen as a disease that may take years or even decades to develop. Taking measures to slow cognitive decline could, potentially help to keep thinking sharp and postpone the onset of full-blown Alzheimer’s by many years.

By ALZinfo.org, The Alzheimer’s Information Site. Reviewed by William J. Netzer, Ph.D., Fisher Center for Alzheimer’s Research Foundation at The Rockefeller University.

Source: C. Raffaitin, MD, C. Feart, PhD, M. Le Goff, MSc, et al: “Metabolic Syndrome and Cognitive Decline in French Elders: The Three-City Study.” Neurology, Feb 2, 2011, Vol. 76, pages 518-525.

Brain Scans Lead to Earlier Alzheimer’s Diagnosis | Fisher Center for Alzheimer's Research Foundation

May 24, 2011

Scientists are moving closer to diagnosing Alzheimer’s disease at an earlier stage using special brain scans. The scans, which are not routinely available in doctors’ offices, should make it easier to know for sure whether someone has Alzheimer’s earlier in its course, when treatments may be more effective and patients can better plan for the future. Currently, the only way to get a definitive diagnosis is to examine the brain after death during an autopsy.

The imaging technique picks up the presence in the brain of plaques, which are made up of clumps of beta-amyloid protein fragments. Plaques are a telltale sign that someone has Alzheimer’s, though their role in the disease is not well understood. Someone may have dementia, but if they do not have plaques, their dementia is due to a condition other than Alzheimer’s.

Between 10 and 20 percent of people who are given a diagnosis of Alzheimer’s turn out not to have the disease when their brains are examined at autopsy. And doctors miss the diagnosis of Alzheimer’s in about a third of patients with early disease and only mild memory loss and other symptoms. Someone who comes to the doctor’s office complaining of depression, for example, may actually be in the early stages of Alzheimer’s.

The imaging techniques involve the use of positron emission tomographic, or PET, scans. They use various dyes that latch on to particles of beta-amyloid in the brain, making it possible to see plaques on the brain scans in living people.

Most recently, an advisory panel to the US Food and Drug Administration recommended approval of an imaging technique developed by Avid Radiopharmaceuticals, pending further study of the technique. The company has developed a brain dye called florbetapir F 18 that attaches to beta-amyloid, which then lights up on PET scans.

In a recent study, florbetapir-PET imaging was performed on the brains of 35 men and women who were in hospice or long-term care facilities and nearing the end of their lives, about half of whom were thought to have Alzheimer’s. Their brains were then examined after they died, to see if the PET scans in the living people were consistent with the findings on autopsy.

In almost all the cases, the living brain scans matched the autopsy findings. One patient who was thought to have Alzheimer’s actually had dementia of other causes. Two others turned out to have Alzheimer’s, though they were given other diagnoses while alive.

Similar scans were performed on 74 young and healthy individuals under age 50. Presumably, their brains would be relatively free of plaque, which turned out to be the case. The study appeared in the Journal of the American Medical Association.

The findings give new weight that such scanning techniques will prove effective in diagnosing Alzheimer’s definitively at earlier stages. Scientists need to do further study to determine how much plaque defines a diagnosis, and doctors need to be trained in carrying out and interpreting test results.

The technique is also being used to assess the effects of various Alzheimer’s drugs in development. By monitoring brain plaques, researchers can determine whether an experimental drug is working by preventing the buildup of beta-amyloid in the brain. Current medications for Alzheimer’s may ease symptoms for a time but do not stop the downward progression of disease.

Additional work needs to be done to evaluate the accuracy of the technique. And doing PET scans with brain dyes is an expensive procedure that cannot be routinely performed in a doctor’s office. Still, the findings add another piece of the puzzle to diagnosing Alzheimer’s disease at earlier stages, potentially allowing patients, family members and doctors to plan for the future more effectively.

By ALZinfo.org, The Alzheimer’s Information Site. Reviewed by William J. Netzer, Ph.D., Fisher Center for Alzheimer’s Research Foundation at The Rockefeller University.
Christopher M. Clark, MD; Julie A. Schneider, MD; Barry J. Bedell, MD, PhD; et al: “Use of Florbetapir-PET for Imaging Beta-Amyloid Pathology.” Journal of the American Medical Association, Vol. 305 (No. 3), January 19, 2011, pages 275-283.
Brain Scans Lead to Earlier Alzheimer’s Diagnosis | Fisher Center for Alzheimer's Research Foundation