Temple researchers work on multiple fronts to advance the diagnosis and treatment of Alzheimer´s disease.
Story by Renee Cree
Alois Alzheimer characterized the disease that would be his namesake more than 100 years ago. Before then, its sufferers struggled without proper diagnoses. The term “senile dementia” was used to define the slow decline of the brain that is characteristic of the illness and was seen as a part of aging until the 1980s, when researchers began using the term Alzheimer’s disease to diagnose the condition.
It has been one of the hardest diseases to find a treatment and a cure for, mainly because its exact cause still is unknown. Existing research suggests that Alzheimer’s could be caused by both genetic and environmental factors, but for the medical community, not knowing its precise cause is frustrating.
And, the healthcare field is in a race against time: The National Institute on Aging estimates that approximately 5.4 million people have Alzheimer’s. That number is expected to more than double by the year 2050.
“The number of Alzheimer’s cases is expected to rise over the next 50 years, and the amount of money it will cost to treat it could bankrupt the health system nationwide,” says Richard Coico, senior associate dean of research in the School of Medicine at Temple. “We need to be more aggressive with our research.”
That is why those at Temple who are examining the disease are working nonstop and exploring myriad options for a treatment, a vaccine and hopefully, a cure, for one of the planet’s most elusive diseases.
“The disease includes environmental, genetic and lifestyle factors. We’re trying to account for all of them in our studies by using a comprehensive approach,” says Domenico Praticò, associate professor of pharmacology and microbiology and immunology in the School of Medicine. “Not everyone gets Alzheimer’s, but by age 85, there’s an approximately 40- to 50-percent chance of its happening. Why is it that certain brains get it and others don’t?”
For more than 20 years, Praticò has been studying neural tissues to learn about how the disease affects the brain.
Most recently, he and his team of researchers published a promising study that revealed that an existing asthma medication, zileuton (Zyflo), could help treat or control the progression of Alzheimer’s. Praticò says that essentially, zileuton cuts the first link in a chain reaction. That drug blocks the activation of enzymes that eventually spur the production of beta amyloid, which, when produced in large quantities, can kill neurons and cause plaques to form in the brain. Those plaques are used to measure the severity of the disease.
“That enzyme is central to the development of the main component of the amyloid plaques found in brains that have Alzheimer’s,” Praticò says. “If you block it, you can stop the plaque from forming and/or getting bigger.”
By using zileuton to block the enzyme, Praticò and his team reduced the buildup of plaques by more than 50 percent.
Praticò is excited about the discovery, primarily because the drug is very close to a clinical trial: It already has been approved by the Federal Drug Administration for inhibiting production of the enzyme without risking harm to the patient.
“There is no drug on the market that treats the damaged cells,” he says. “This research shows us that the enzyme can be controlled with pharmaceuticals, and since this drug has been approved already, we can proceed quickly with clinical trials.”
Praticò also has begun work with Magid Abou-Gharbia, associate dean of research in the School of Pharmacy and director of the Moulder Center for Drug Discovery Research, to test 12 new compounds that can act as inhibitors of the enzyme and ultimately stop the formation of plaques associated with Alzheimer’s.
Praticò says that any drug used for the treatment of Alzheimer’s needs to target the damaged cells in the brain, but the blood-brain barrier acts as a filter to keep them out. Abou Gharbia is synthesizing smaller molecules to pass through the blood-brain barrier.
“We are making novel compounds that can be more effective and can reach the brain better than older drugs,” he says.
Together, Praticò and Abou-Gharbia have applied for several grants to further study the effectiveness of these compounds.
“Current therapies on the market treat the symptoms, but not the disease itself,” Praticò says. “They mostly help with memory loss, but that’s like taking headache medicine when you have a tumor.”
In addition to pharmaceutical options, Praticò and his team also are testing how lifestyle changes, such as diet and exercise, might slow or reverse the damage the disease causes.
In 2009, Praticò found that a diet rich in methionine—an amino acid typically found in some foods, many of which are considered healthful, including red meats, fish, beans, eggs, garlic, onions, yogurt and seeds—might increase the risk of developing Alzheimer’s disease. He based his hypothesis on existing studies that showed that as the methionine level gets too high, the body reacts by turning it into another amino acid called homocysteine. High levels of homocysteine in the blood have been linked to a higher risk of dementia.
The researchers found that higher levels of homocysteine existed in models that also had higher amounts of amyloid plaques. However, Praticò released a study last year that found that switching to a diet lower in methionine could slow or, in some cases, reverse the damage done in the brain by a methionine-rich diet.
In another department at Temple, Diana Woodruff-Pak, professor of psychology in the College of Liberal Arts and professor of neurology in the School of Medicine, hopes to diagnose Alzheimer’s with the blink of an eye.
From left: Magid Abou Gharbia, associate dean of research in the School of Pharmacy and director of the Moulder Center for Drug Discovery Research at Temple; Domenico Praticò, associate professor of pharmacology and microbiology and immunology in the School of Medicine; and Diana Woodruff-Pak, professor of psychology in the College of Liberal Arts and professor of neurology in the School of Medicine; are each taking a different path toward an Alzheimer's treatment and cure.
For 25 years, Woodruff-Pak has been using a model called “eyeblink classical conditioning” in her research. Basically, this model studies the blinking reflex in the same way that Ivan Pavlov studied the salivation reflex in dogs from 1891 to 1900. At first, Pavlov would ring a bell from the time a dog was served food until the food was taken away. He found that soon the dog would salivate whenever a bell rang, whether or not food was present, caused by the dog’s strong connection between the bell and the food. Woodruff-Pak is testing a similar form of associative learning that involves blinking.
In the mid-1980s, she spent two years as a visiting professor at Stanford University in California, working in the lab of Richard F. Thompson. Thompson’s group was mapping the neuronal circuits behind eyeblink conditioning and had demonstrated that the action became impaired with age.
Woodruff-Pak theorized that since the neurotransmitter system that affects muscle reaction and concentration is severely impaired in people with Alzheimer’s, the eyeblink response also would be impaired in people with Alzheimer’s.
“I was able to test the eyeblink response in patients with Alzheimer’s, and my team and I found that they were dramatically impaired in this simple form of learning,” she says. “At the time, neurologists thought only higher cortical functions were impaired. Our result was a revelation.
“In our work, we have documented that eyeblink conditioning is a powerful diagnostic tool for early detection of the disease,” she continues. “We need to treat the disease early, when it begins to lay down pathology in the brain—which takes place in patients in their late 40s and early 50s—when they are still functioning well and do not know that the illness is progressing.”
In two large studies, Woodruff-Pak and her team demonstrated that some adults in this age group are impaired in their eyeblink conditioning and that it could be used as a more cost-effective and less-invasive diagnostic tool for early detection of Alzheimer’s. She also plans to study the relationship between eyeblink conditioning performance and more traditional diagnostic tests—such as PET scans and cerebral spinal fluid measures—to detect levels of beta amyloid during middle age. Beta amyloid comprises the plaques in brains affected by Alzheimer’s.
Roles of Antibodies
Woodruff-Pak is not only looking for methods of early detection; she also is searching for a preventative vaccine. Collaborating with Richard Coico, she is testing immunization strategies to vaccinate against the buildup of beta amyloid.
In conventional vaccinations, the goal is to stimulate the immune system to generate antibodies that will protect the individual from disease. Woodruff-Pak and Coico are testing a vaccination with a small portion of beta amyloid to induce antibodies that will react
“If you induce an immune response to beta amyloid, there is strong evidence from multiple laboratories, including ours, that the antibodies generated significantly reduce the incidence of amyloid plaques in the brain,” Coico says. “Our goal is to determine whether such an effect correlates with the improvement of cognitive deficiencies seen in this model.”
Those studying Alzheimer’s at Temple agree that one of the most frustrating aspects of seeking a treatment for Alzheimer’s is ensuring that it focuses on all aspects of the disease, from healing lesions on the brain to restoring cognitive ability.
“We can test for lesions in the brain and if these treatments clear them, but we also must test if and how patient behavior will be affected by clearing the lesions,” Praticò says. “We must address the clinical aspect—the improvement in the ability to learn and to remember.”
In addition to Alzheimer’s research conducted in laboratories such as Praticò’s and Woodruff-Pak’s, the School of Medicine received an $11.8 million grant from the National Institutes of Health (NIH) to create laboratory space that will house, in part, the Institute for Translational Neuroscience. The institute will enable future collaborations between basic neuroscience researchers and their clinical counterparts at Temple University Hospital.
The goal is to bring together researchers from various departments in the School of Medicine to focus on four key areas of research—neuroAIDS, inflammation, neuropharmacology and neurodegeneration—in order to develop effective therapeutic strategies that will target neurological conditions.
“Every grant application that is submitted to NIH must show clinical applications of research,” Coico says. “As researchers, we have to be able to show how what we’re studying is going to benefit patients and how it’s going to make their lives better. Alzheimer’s research is no different.”
For Woodruff-Pak, the need to improve the lives of those with Alzheimer’s has never been more urgent. Her mother, diagnosed with the illness years ago, was placed in an assisted living facility for older adults with Alzheimer’s this year. She keeps this in mind as she continues her research.
“In May 2010, the Alzheimer’s Association reported that the cumulative costs of caring for Alzheimer’s over the next 40 years would exceed $20 trillion unless treatments are discovered,” she explains. “But the monetary figures fail to convey the tragic loss of self and the hardships of families that are the human faces of the disease. My longtime scientific career goals to diagnose, treat and prevent Alzheimer’s have become personal passions.”
Renee Cree is a staff writer in Temple’s University Communications department.
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