USF laboratory study shows drug targets chaperone Hsp70 to reduce Alzheimer’s protein

Chad Dickey's team at the USF Health Byrd Alzheimer's Institute focuses on manipulating with drugs or gene therapy the chaperone proteins that control the fate of the the Alzheimer's protein tau.

Tampa, FL (September 30, 2009) -- Inhibiting the protein Hsp70 rapidly reduces brain levels of tau, a protein associated with Alzheimer’s disease when it builds up abnormally inside nerve cells affecting memory, neuroscientists at the University of South Florida found. The study is reported online today in the Journal of Neuroscience.

“Now that we’ve discovered that targeting the chaperone protein Hsp70 can clear tau, it could be helpful in finding more effective drugs for Alzheimer’s disease,” said the study’s senior author Chad Dickey, PhD, assistant professor of molecular medicine who works out of the Byrd Alzheimer’s Institute at USF Health “The therapeutic strategy may also be applicable to other neurodegenerative diseases involving Hsp70, such as Huntington disease, Amyotrophic lateral sclerosis (ALS), and some cancers.”

Hsp70 is a one of several “chaperone” proteins that supervises the activity of tau inside nerve cells. The normal function of tau is to support the structure of nerve cells, much like the skeleton provides a scaffold to support the body. Tau is inside nerve cells, while another hallmark protein associated with Alzheimer’s, beta amyloid, is outside the neurons.

Working with researchers at the University of Michigan, the USF team tested the effects of several compounds on Hsp70 in cell models and brain tissue from mice genetically modified to develop the memory-choking tau tangles. Some compounds activated Hsp70, and others were Hsp70-inhibitors.

One of the more effective Hsp70-inhibitor drugs the researchers discovered was a derivative of methylthioninium chloride, or Rember™, the first experimental medication reported to directly attack the tau tangles in patients with Alzheimer’s disease. Rember™ was heralded as a major development in the fight against Alzheimer’s when results in early clinical trials were announced last year at the International Conference on Alzheimer’s disease.

“But Rember™ and its derivatives do have some inherent problems; they’re not very potent so effective therapy would require fairly high doses, Dickey said.

“The drug does help prevent the protein (tau) from clumping together, but that in itself doesn’t mean it’s actively getting rid of the toxic tau,” he said. “Now that we know Hsp70 is a target of Rember™, we can develop similarly-acting drugs that will more specifically target this chaperone protein in affected areas of the brain, resulting in fewer side effects.”

The USF researchers originally thought activating Hsp70 would direct the chaperone protein to decrease the tau gone bad -- preventing tau from stacking up into tangles inside cells involved in memory and destroying them. But instead of restoring tau to its normal supportive function, activating Hsp70 actually led to tau’s preservation and even more accumulation, Dickey said. “Basically we think the chaperone binds to the tau, and somehow in the process of trying to fix things decides to keep holding onto tau when it shouldn’t. So, activating Hsp70 is not necessarily what we want to do; we ultimately want to inhibit Hsp70 to promote the release or clearance of tau …to kill the bad tau.”

Dr. Dickey emphasizes that problems with Hsp70 alone do not cause Alzheimer’s. It likely develops from a convergence of various factors in the brain, he said, including deposits of the other featured Alzheimer’s protein beta amyloid, or a genetic defect; disruption of cell signaling; a breakdown in the neuron’s support structure, and then accumulation of tau into the memory-choking tangles.

Dr. Dickey’s team at USF focuses on how to manipulate with drugs or gene therapy the chaperone proteins that regulate tau’s fate – determining whether it’s preserved or cleared from the brain. The University of Michigan team works on identifying and developing compounds that may be effective against Alzheimer’s disease and other tauopathies.

The study was supported by the national Alzheimer’s Association, the National Institute on Aging, the Abe and Irene Pollin Fund for CBD Research from CurePSP: The Society for Progressive Supranuclear Palsy, and the National Institute of Neurological Disorders and Stroke.

The study’s other authors were Umesh Jinwal (lead author), Yoshinari Miyata, John Koren III, Jeffrey Jones, Justin Trotter, Lyra Chang, John O’Leary, David Morgan, Daniel Lee, Cody Shults, Aikaterini Rousaki, Edwin Weeber, Erik Zuiderweg, and Jason Gestwicki.

- USF Health -

USF Health is dedicated to creating a model of health care based on understanding the full spectrum of health. It includes the University of South Florida’s colleges of medicine, nursing, and public health; the schools of biomedical sciences as well as physical therapy & rehabilitation sciences; and the USF Physicians Group. With more than $380.4 million in research grants and contracts last year, USF is one of the nation’s top 63 public research universities and one of 39 community-engaged, four-year public universities designated by the Carnegie Foundation for the Advancement of Teaching. For more information, visit www.health.usf.edu

University of South Florida neuroscientists have been awarded a $1.5 million federal grant to evaluate a new treatment, human umbilical cord blood cells (HUCBC), in a mouse model for Alzheimer's disease.

The five-year grant from the National Institute on Aging was awarded to Jun Tan, MD, PhD, Robert A. Silver Chair and Director of the Rashid Laboratory for Developmental Neurobiology at the Silver Child Development Center, USF Department of Psychiatry. The study co-investigators are Paul Sanberg, PhD, DSc, director of the Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, and David Morgan, PhD, professor in the Department of Molecular Pharmacology and Physiology and chief scientific officer of the Byrd Alzheimer Institute at USF Health.

Recent USF studies have shown that immunity can be transferred using human umbilical cord blood cells, which improves the pathology associated with Alzheimer’s disease in a mouse model. Other studies have demonstrated that a specific immune system suppression is correlated with significantly reduced abnormal levels of the beta amyloid protein linked to Alzheimer’s disease.

“This new NIH study will continue to build on our understanding of the HUCBC’s mechanism behind improvement in Alzheimer’s disease,” Dr. Tan said. “It will help provide a better understanding of brain immune cells called microglia, which promote brain inflammation in Alzheimer’s disease.”

Dr. Tan and his colleagues previously demonstrated that once a specific molecule, CD40, on the surface of these microglia cells becomes activated by its partner, CD40L (CD40 ligand), the scene is set for a cascade of events leading to brain inflammation that injures the brain’s neurons. They also showed that the trigger for this harmful immune response can be blocked by specific antibodies.

In this study, Dr. Tan and his team plan to test the hypothesis that HUCBC could reduce the interaction between the CD40L molecule and its CD40 target, which in turn would decrease Alzheimer’s pathology in the brain. The experiments will be performed on (transgenic) mice genetically modified to develop memory problems mimicking Alzheimer’s disease as they age.

Furthermore, the researchers plan to create a cocktail combining the precise molecules they believe are the key players behind HUCBC’s beneficial effects. “We will give the compound to these transgenic mice to assess the possibility of bypassing the need for HUCBC and making future therapies more cost effective,” Dr. Tan said.

"This approach shifts the focus from treating symptoms of Alzheimer's disease to treatments that slow down the disease or prevent it altogether.” Dr. Tan said. “Our long-term goal is to move this combination treatment into phase I human trials for patients with mild to moderate Alzheimer’s disease.”

    Ataxia patients Avery Zaritsky, Kyle Bryant and Nygel Lanz spoke at USF Health last week about the need for more research into Friedreich's and other ataxias.

     Just a few years ago, living with ataxia was so much lonelier.

     Avery Zaritsky was diagnosed with the disease at 19. For a long time, she and her husband, Paul, felt it was, at least medically, them against the world. Doctors even told them not to have children.

     "Eight or nine years ago, we were all on our own," said Dr. Paul Zaritsky, a Tampa dentist. "Now we have hundreds of scientists backing us up."

     Patients and researchers voiced that same sense of optimism repeatedly at USF at how rapidly research into Friedreich's and other ataxias has started to show promise. USF hosted a series of events last week that will benefit the USF Ataxia Research Center and FARA, the Friedreich's Ataxia Research Alliance.

     Friedreich's is a rare neuromuscular disorder which affects the body's ability to balance, as well as causing muscle weakness and other problems. There is no known treatment or cure.

     But just in the last five years, a host of promising research avenues have blossomed, said Jennifer Farmer, executive director of FARA, at a research symposium last week. Just since 2004, research has gone from three different avenues of attack to nine, she pointed out.

     "This is why we're so excited," she said. "We need multiple shots on goal."

     Among those shots is research by Dr. Theresa Zesiewicz, professor of neurology and director of the USF Ataxia Research Center. Dr. Zesiewicz is studying how the smoking cessation drug varenicline could be used as a treatment to help ataxia patients with balance difficulties.

     Dr. Zesiewicz wowed last week's crowd when she showed videos showing patients with limited balance and substantial difficulty walking before taking varenicline and notable improvements afterwards. She cautioned that those results are preliminary and that the drug has substantial side effects.

     Still, such efforts are among those that give Farmer hope.

     "I like to think of the last decade as the decade of progress," she said.

     Dr. Stephen K. Klasko, dean of the USF College of Medicine and CEO of USF Health, told the group that research is nearing the final step.

      "We know a lot about this disease," he said. "What we don't know yet is how to stop it."

      Dr. Stephen Klasko, dean of the USF College of Medicine, talks about USF's ataxia research.

     But that day will come, he said.

      "Thank you for your courage and your patience," Dr. Klasko said to the ataxia patients present. "We will beat this."

        That can't happen soon enough for patients like Kyle Bryant, who was diagnosed with Friedreich's ataxia at age 17.

"I think Friedreich's ataxia gives us all a sense of urgency," Bryant said. "I don't know where I will be in the next five years. I will never be as able as I am now."

Jennifer Farmer, executive director of FARA; Dr. Theresa Zesiewicz, director of the USF Ataxia Research Center; Dr. Clifton Gooch, USF neurology chair; Dr. Jeffrey Krischer, director of the USF Pediatrics Epidemiology Center and principal investigator of the NIH-funded Rare Diseases Clinical Research Network Data Management and Coordination Center

     Yet Bryant already had to give up bicycling, switching to a recumbent trike that is easier to balance on. He's made the most of that: in 2006, he founded a group called Ride Ataxia, a group that has biked 3,300 in the last two years, helping raise $700,000 for ataxia research.

"We were totally devastated in the beginning," Bryant said at USF last week. "We've taken an amazing journey and turned 180 degrees, and experienced some amazing things that we wouldn't have otherwise."

Still, Bryant feels time is short.

"We need to do it fast," he told the audience at last week's symposium. "We need to do it hard. We need to do it now."

-- Story by Lisa Greene, USF Health Communications; Video by Anne DeLotto Baier, USF Health Communications; Photos by Eric Younghans, USF Health Communications

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- Energizing Research for a Cure
- From wheelchair to walking, ataxia patient finds hope through USF study

Susan Wier participated in a pilot study at the USF Ataxia Research Center, which led to a dramatic improvement in her ataxia symptoms.

Up until 1991, Susan Wier’s life was pretty typical, filled with the satisfying balance of wife, mother and nurse.

But over the course of several years year, Susan lost her ability to control her own coordination. Three to four times a day, she felt dizzy and lightheaded, and her speech turned drawn and guttural. Every time she walked, even with the aid of a cane or walker, she walked with a wide stance and a wobbling gait. The balance problems caused further injuries, like a broken foot bone, a broken wrist bone and lots of bruising. Eventually, Susan and her family accepted that she would be confined to a wheelchair.

The lack of mobility and control of her own movements limited every activity. Her nursing career ended early, simple tasks became exhausting, and she had to give up one of her favorite pastimes, reading, because uncontrollable eye movements prevented her from focusing. She became dependent on her family for nearly everything, as her husband and children struggled with how to provide the care Susan needed while helping her maintain some independence.

Watch video of Susan before and after investigational treatment:

Susan was familiar with these symptoms because she watched her grandfather suffer and die in his early 70s. In addition, four out of five aunts and uncles were clearly affected by similar symptoms and all died before their late 70s, and three cousins who experienced the symptoms have since passed away, one at the age of 45.

Her family called the mystery illness “our family curse.”

“Our family has a history of eight generations of this,” she said. “And I have three sons and grandchildren that I worry about every day, not only for their health, but for the strain that my deteriorating health and long-time care may have on the quality of their lives.”

This fear pushed Susan to finally find an answer.  In 1991, she, some of her siblings and a cousin participated in an NIH study looking for the gene responsible for a rare disease called ataxia.  The result: the family had the gene and Susan, one sibling and a cousin had ataxia.

“But now we had a name for it,” she said. “The effects of this crippling disease are something I had been acutely aware of since before I knew it by name – before I could no longer walk without assistance and before I knew it was hereditary and feared for my children and grandchildren.”

Finally having a diagnosis has helped Susan and her family cope, but only so much because ataxia has no cure and managing the symptoms is limited. To learn more about ataxia and to share her family’s story, Susan joined the West Central Florida Ataxia Support Group, which offered a lot of practical, emotional and inspirational help. At one of the group’s meetings, Susan heard about a promising study starting at the USF Ataxia Research Center (USF ARC).  Wasting no time, she called and, after finding out everything she could about the research and meeting the physicians there, became the first volunteer for a new study testing the effectiveness of the drug varenicline (a medication used to quit smoking) in reducing the severity of ataxia symptoms.

Right: Dr. Theresa Zesiewicz, director of USF ARC, tests Susan's reflexes. Left: Seok Hun Kim, PT, PhD, assistant professor in the School of Physical Therapy & Rehabilitation Sciences, assists Susan as she walks across GaitRite mat in the school's Human Functional Performance Lab.

Watch video (above) of Susan walking across a GaitRite Mat, which tests walking speed, stride length and other gait characteristics. The information helps USF physical therapists evaluate whether therapies such as exercise and medications are effective over time in patients with ataxia or other disorders affecting balance and movement.

The results were dramatic, nearly a complete turnaround. Susan experienced what she describes as an 80-percent improvement in her symptoms and lost 40 pounds because of her increased activity. She even noticed an improvement in her depression, a symptom she hadn’t really acknowledged until she felt so much better.

“I didn’t realize how depressed I was,” she said. “Now I approach every new day with a can-do attitude. It is my sincere hope that much can be learned from this study. Dr. Z. (Theresa Zesiewicz) and her team have been phenomenal. I know that the medicine is not a cure. I still have ataxia, but the symptoms are drastically reduced.”

Susan chats with USF physical therapist Jeannie Stephenson, PT, MS, NCS, who helped evaluate her gait.

Today, Susan still uses a cane, but her mobility is vastly improved. In fact, from lack of use, her wheelchair is now parked in a corner with a sheet over it. Her speech still occasionally falters, but mostly she converses clearly. And the icing on the cake is that she is reading again.

“With this new sense of hope and treatment, I have dedicated myself to helping others live with ataxia and to assisting the medical community in curing it for the generations to come,” Susan said. “My hope is that the comprehensive studies from USF ARC may benefit not only ataxia, but other neurological diseases as well.”

Story by Sarah A. Worth, USF Health Communications
Photos by Eric Youghans, USF Health Communications

USF Ataxia Research Center at forefront of helping patients battling little-known neurological disease

The faces of ataxia are diverse. Shelby Reynolds, left, has Friedreich's ataxia, while Susan Wier lives with spinal cerebellar ataxia.

Within the course of several years Susan Wier went from being a vibrant wife, mother, and nurse to a woman nearly confined to a wheelchair because she could no longer control her mobility (to read Susan's story, click here).

A family history provided a hint of what the early symptoms meant was to come, but it wasn’t until Susan participated in a National Institutes of Health study that she confirmed what was wrong: she had ataxia.  And it wasn’t until turning to the USF Ataxia Research Center last year and participating in a promising study there that she experienced a dramatic improvement in her symptoms. Within a short time, she transitioned from needing a wheelchair for getting around to only occasionally requiring her husband’s arm for support.

Why did Susan have to be subjected to this roller coaster ride, taking her from typical to debilitated to almost normal again? Why should anyone have to go through that?

Ataxia is so destructive, yet little known by the general population. Even in the field of medicine, patients can go undiagnosed and misdiagnosed for years, because physicians may not routinely consider this rare neurological problem when trying to help patients determine what has halted their ability to control their own movements.

That is why the USF Ataxia Research Center (USF ARC) has been so successful. Its sole focus is to make use of multiple areas of science to help patients with ataxia and their families while educating the public and other physicians about the disease (to read more about the USF-ARC and its team of experts, click here).

The USF ARC team takes a multidisciplinary approach to helping patients with ataxia.

USF-ARC has become a model for other academic medical centers because it looks at the whole picture for treating ataxia, said Theresa Zesiewicz, MD, director of USF ARC and professor of neurology at USF. Basic scientists are studying the physiology and genetics of the disease. Pharmacologists are testing responses to medicines at the molecular level. Physical therapists are helping patients regain some control over their movements. And a team of physicians is treating ataxia patients, even providing them access to much needed, and so far very hopeful, clinical studies.

“We are very unusual because we are one of the very few ataxia centers in the country. In addition we offer a full translational approach,” Dr. Zesiewicz said. “That means we have experts in basic science, physical therapy and clinical areas who follow patients along each step of their care. Patients, as well, follow each of these areas, making use of current research and successful treatments for their symptom management.”

USF neurologist Dr. Theresa Zesiewicz directs the USF ARC.

For example, she said, the USF ARC team envisioned very promising possibilities for varenicline (a smoking cessation drug known as Chantix), which immediately opened a door for hosting a pilot clinical trial.

This smaller study has led to two randomized, placebo-controlled clinical trials examining the potential of Chantix as the first effective treatment for ataxia.  Dr. Zesiewicz is the principal investigator for both, which recently began enrolling patients at USF and other universities across the country. One trial, sponsored by Friedreich’s Ataxia Research Alliance (FARA), is looking at Chantix in adults with Friedreich’s ataxia (FA), a particularly devastating neuromuscular form of the disease that usually strikes children and teenagers. The other trial, sponsored by the National Ataxia Foundation and the Bobby Allison Ataxia Research Alliance, is focusing on adults with spinocerebellar ataxias.

Dr. Zesiewicz and colleagues at the USF ARC suspect that Chantix may improve ataxia symptoms by targeting something gone awry with nicotinic receptors in the nervous system.

Those with FA or other types of ataxia should not to begin Chantix without physician monitoring, Dr. Zesiewicz cautioned, because the prescription drug has caused serious side effects in some who have used it to stop smoking.

“As with all research, even if this particular medication isn’t ‘the one,’ our studies will help us better understand the underlying mechanism of ataxia, which could lead to a finding for another hopeful treatment or cure,” Dr. Zesiewicz said.

Research like that conducted in the pharmacology laboratory of USF's Dr. Lynn Wecker seeks to understand the underlying mechanisms of ataxia.

WHAT IS ATAXIA?
Ataxia is a group of neurological diseases in which a person’s movement is uncoordinated. There are several types of ataxia, each with its own severity, but all are characterized by difficulty in controlling balance and movement.

The most obvious symptom is an unbalanced gait, which often makes ataxia patients appear drunk. Speech and eye movements are additional symptoms, and in severe cases, patients may experience swallowing and respiratory problems.

Currently, there is no proven treatment or cure for ataxia.  Though not terminal, the disorder is usually life shortening. Its victims become debilitated -- slowly reduced to walkers, then wheelchairs, and eventually bedridden.

Dr. Zesiewicz examines Shelby Reynolds, 10, who has Friedreich's ataxia.

Many forms of ataxia are hereditary, while others may be induced by medications, infections, toxins or alcoholism.  In the type of ataxia Wier inherited -- spinocerebellar ataxia type 3 -- the gene associated with the ataxia is located on autosomal, or non-sex, chromosomes (SCA 3) and, therefore, affects males and females equally.

For many families, finally getting a diagnosis eases the burden of dealing with ataxia.  They can finally look up information about the disease and find support groups. That is one of the main reasons the USF ARC has the mission of educating the public and physicians about all forms of cerebellar ataxia.

“The response to our ARC has been overwhelming,” Dr. Zesiewicz said. “Patients spearheaded getting the word out through blogs and the internet. This tactic is helping us discover new and effective approaches to better understand and treat cerebellar ataxia, while also searching for a cure.”

The USF ARC works with all types of ataxia but offers a special focus on FA, a progressive neuromuscular disease that typically causes its young victims to be wheelchair bound by their early 20s. “It’s devastating because at a time of life when these kids should be focusing their energies on college and careers, their major goal is staying out of a wheelchair,” Dr. Zesiewicz said.

A series of events is scheduled August 27 through 29 to benefit USF ARC and FARA. It begins with a scientific symposium open to the community Thursday evening, Aug. 27, and culminate with the FARA Energy Ball on Saturday evening, Aug. 29.

Story by Sarah A. Worth, USF Health Communications

Photos by Eric Younghans, USF Health Communications

Research may have implications for other neurological disorders affecting balance

Tampa, FL -- An upcoming  symposium at USF Health will bring together scientists, clinicians and patients to discuss promising new research for Friedreich’s ataxia and other ataxias, a group of degenerative diseases of the nervous system that adversely affect balance, coordination and movement.

“Understanding Energy for a Cure” will be held 6:15 to 8 p.m. on Thursday, August 27, in Room 1013 at the Morsani Center for Advanced Healthcare at USF Health, 13330 USF Laurel Drive, Tampa, FL 33612. The symposium, sponsored by the Friedreich’s Ataxia Research Alliance (FARA) and the USF Ataxia Research Center (ARC), is free and open to the public.

Dr. Jeffrey Krischer, professor and director of the USF Pediatrics Epidemiology Center, will speak on “The Challenges and Promise of Rare Diseases Research.”  Dr. Krischer is the principal investigator for a major National Institutes of Health data coordinating center that supports the Rare Diseases Clinical Research Network, which is addressing the complexities of diagnosing and treating a variety of rare diseases, including ataxias.

Other speakers will be Dr. Theresa Zesiewicz, professor of neurology and director of the USF ARC; Jennifer Farmer, executive director of FARA; and Ron Bartek, president and founder of FARA.  Topics will cover new research, the care and management of ataxia, with an emphasis on Friedreich’s; and patient advocacy. Dr. Stephen Klasko, CEO for USF Health and dean of the College of Medicine, will moderate a panel discussion on the patient’s perspective of ataxia.

“Research investigating the underlying molecular mechanisms of Friedreich’s and spinocerebellar ataxia may lead not only to treatments for ataxias, but also to more effective therapies for imbalance caused by stroke, tumors and toxins,” Dr. Zesiewicz said.

The USF ARC provides care for patients suffering from imbalance and ataxia, while conducting both basic science and patient-oriented research.  The center has a special focus on Friedrich’s ataxia, a debilitating neuromuscular disease that typically strikes children and teenagers and leaves them wheelchair bound by their early 20s.

The center is currently spearheading several clinical trials in Friedreich’s and spinocerebellar ataxias, partnering with other universities and national organizations, including FARA, the National Ataxia Foundation and the Bobby Allison Ataxia Research Alliance, to bring promising medications to human testing.

For more information, please call (813) 974-5909.

About USF Health
USF Health is dedicated to creating a model of health care based on understanding the full spectrum of health. It includes the University of South Florida’s colleges of medicine, nursing, and public health; the schools of biomedical sciences as well as physical therapy & rehabilitation sciences; and the USF Physicians Group. With more than $360 million in research grants and contracts last year, USF is one of the nation’s top 63 public research universities and one of 39 community-engaged, four-year public universities designated by the Carnegie Foundation for the Advancement of Teaching.

About FARA
The Friedreich's Ataxia Research Alliance's (FARA) mission is to marshal and focus the resources and relationships needed to cure FA by raising funds for research, promoting public awareness, and aligning scientists, patients, clinicians, government agencies, pharmaceutical companies and other organizations dedicated to curing FA and related diseases.

Study has implications for postoperative elderly patients at risk for Alzheimer’s disease

Tampa, FL (Aug. 11, 2009) -- A 65-year-old women goes into the hospital for routine hip surgery. Six months later, she develops memory loss and is later diagnosed with Alzheimer’s Disease. Just a coincidence? Researchers at the University of South Florida and Vanderbilt University don’t think so. They suspect that the culprit precipitating Alzheimer’s disease in the elderly women may be a routine administration of high concentrations of oxygen for several hours during, or following, surgery – a hypothesis borne out in a recent animal model study.

Dr. Gary Arendash of the Florida Alzheimer’s Disease Research Center at USF and Dr. L. Jackson Roberts II at Vanderbilt University used mice genetically altered to develop abnormal levels of the protein beta amyloid, which deposits in the brain as plaques and eventually leads to Alzheimer’s-like memory loss as the mice age. They found that young adult Alzheimer’s mice exposed to 100-percent oxygen during several 3-hour sessions demonstrated substantial memory loss not otherwise present at their age. Young adult Alzheimer’s mice exposed to normal air had no measurable memory loss, and neither did normal mice without any genetic predisposition for Alzheimer’s disease.

The authors suggest that people genetically predisposed to Alzheimer’s disease or with excessive amounts of beta amyloid in their brains are at increased risk of developing the disease earlier if they receive high concentrations of oxygen, known as hyperoxia. Their study is published online this month in NeuroReport.

“Although oxygen treatment beneficially increases the oxygen content of blood during or after major surgery, it also has several negative effects that we believe may trigger Alzheimer’s symptoms in those destined to develop the disease,” said USF neuroscientist Arendash, the study’s lead author. “Our study suggests that the combination of brain beta amyloid and exposure to high concentrations of oxygen provides a perfect storm for speeding up the onset of memory loss associated with Alzheimer’s Disease.”

USF neuroscientist Gary Arendash was the study's lead author.

While postoperative confusion and memory problems are common and usually transient in elderly patients following surgery, some patients develop permanent Alzheimer’s-like cognitive impairment that remains unexplained. Recent studies have indicated that general anesthesia administered during surgery may increase a patient’s risk of Alzheimer’s disease, but the laboratory studies did not use animals or people predisposed to develop the disease.

“Postoperative memory loss can be a fairly common and devastatingly irreversible problem in the elderly after major surgical procedures,” said Roberts, an MD who holds an endowed chair in Pharmacology at Vanderbilt University School of Medicine. “There has been much speculation as to the cause of this memory loss, but the bottom line is that no one really knows why it happens. If all it takes to prevent this is reducing the exposure of patients to unnecessarily high concentrations of oxygen in the operating room, this would be a major contribution to geriatric medicine.”

The USF-Vanderbilt study looked at 11 young adult mice genetically modified to develop memory problems as they aged, mimicking Alzheimer’s disease. After behavioral tests confirmed the mice had not yet developed memory impairment at age 3 months – about age 40 in human years – the researchers exposed half the Alzheimer’s mice to 100-percent oxygen for three hours, three times over the next several months. The protocol was intended to replicate initial and supplemental exposures of elderly patients in hospital operating rooms and recovery suites to high concentrations of oxygen. The other half of the mice were exposed to 21-percent oxygen, the concentration of oxygen in typical room air.

When researchers retested the mice after the final gas exposure, they found that Alzheimer’s mice exposed to 100-percent oxygen performed much worse on tests measuring their memory and thinking skills than the Alzheimer’s mice exposed to normal room air. In fact, the Alzheimer’s mice exposed to room air demonstrated no memory loss. Moreover, exposure of young adult mice without beta amyloid protein deposited in their brains to 100-percent oxygen did not adversely affect their memories. This is consistent with studies in humans showing that exposure of young adults to high concentrations of oxygen has no harmful effects on memory.

The researchers also demonstrated that even a single 3-hour exposure to 100-percent oxygen caused memory deficits in the Alzheimer’s mice. Furthermore, when they examined the brains of these mice, they found dramatic increases in levels of isofurans, products of oxygen-induced damage from toxic free radicals. The increase was not present in the brains of normal control mice exposed to the single hyperoxia treatment.

How might high concentrations of oxygen hasten memory impairment in those destined to develop Alzheimer’s disease? The researchers suggest the striking increase of isofurans during surgery may be one triggering mechanism, particularly in cardiac bypass surgery where very high blood oxygen levels are routinely attained and permanent memory loss often occurs months after the surgery. Secondly, exposure to high oxygen concentrations prompts abnormal swelling of brain cell terminals that transmit chemical messages from one brain cell to another and may further disrupt already frayed nerve cell connections in those at risk for Alzheimer’s. Third, high concentrations of oxygen combined with beta amyloid plaques constricts blood vessels and decreases blood flow to the brain more than either one alone.

The authors caution that the study in mice may or may not accurately reflect the effects of hyperoxia in human surgery patients.

“Nonetheless, our results call into question the wide use of unnecessarily high concentrations of oxygen during and/or following major surgery in the elderly,” Roberts said. “These oxygen concentrations often far exceed that required to maintain normal hemoglobin saturation in elderly patients undergoing surgery”.

Arendash published initial evidence in 1987 that Alzheimer’s disease starts in the brain several decades before memory loss occurs. His research focuses on developing promising therapeutics in Alzheimer’s mice that can quickly be transferred to human clinical trials. Roberts, an expert on the role of free radicals and oxidative injury in disease, has discovered novel products of free radical damage that may be associated with several age-related brain dysfunctions. Also participating in the hyperoxia study were Dr. Takashi Mori of Saitama Medical University (Japan) and Dr. Kenneth Hensley of the Oklahoma Medical Research Foundation.

The study was supported by grants within the Florida Alzheimer’s Disease Research Center, a statewide project sponsored by the National Institute on Aging, and a National Institutes of Health Merit Award to Dr. Roberts.

An estimated 10 million baby boomers will develop Alzheimer's disease in their lifetime. The disease usually begins after age 60, and risk rises with aging. The direct and indirect cost of Alzheimer's disease in the United States is a staggering $150 billion a year, according to the national Alzheimer’s Association.

- USF Health -
USF Health is dedicated to creating a model of health care based on understanding the full spectrum of health. It includes the University of South Florida’s colleges of medicine, nursing, and public health; the schools of biomedical sciences as well as physical therapy & rehabilitation sciences; and the USF Physicians Group. With more than $360 million in research grants and contracts last year, USF is one of the nation’s top 63 public research universities and one of 39 community-engaged, four-year public universities designated by the Carnegie Foundation for the Advancement of Teaching.

- Vanderbilt University Medical Center -
Vanderbilt Medical Center (VMC) is a comprehensive healthcare facility dedicated to patient care, research, and biomedical education. Its reputation for excellence in each of these areas has made Vanderbilt a major patient referral center for the Mid-South. Each year, people throughout Tennessee and the Southeast choose Vanderbilt for their health care needs, not only because of its excellence in medical science, but also because the faculty and staff are dedicated to treating patients with dignity and compassion. Vanderbilt's mission is to advance health and wellness through preeminent programs in patient care, education, and research.

The study by scientists from Laval University and USF has implications for the development of future cell therapies for Parkinson's and Huntington's disease

July 20, 2009 -- Results of a new study published online this week in the Proceedings of the National Academy of Sciences question the long-term effects of transplanted cells in the brains of patients suffering from Huntington’s disease. The study, conducted by Dr. Francesca Cicchetti of Laval University in Québec, Canada, Dr. Thomas B. Freeman of the University of South Florida (USF) Department of Neurosurgery and Brain Repair, Tampa, FL, and colleagues provides the first demonstration that transplanted cells fail to offer a long-term replacement for degenerating neurons in patients with Huntington’s disease.

Huntington’s disease is a neurodegenerative disease of genetic origin that targets a particular type of neuron. The loss of these neurons is responsible for the appearance of involuntary movements as well as cognitive and psychiatric impairments. Over a decade ago, USF neurosurgeon Dr. Freeman initiated a clinical trial of neural cell transplantation in patients with Huntington’s disease in an attempt to alleviate the devastating symptoms that characterize this disease.

Some patients demonstrated some mild, transient clinical benefits that lasted for about two years. However, the loss of functional recovery after this time indicated that graft survival and functionality may be jeopardized long-term.

Study senior co-author Dr. Thomas Freeman, a professor in the USF Department of Neurosurgery and Brain Repair, is a leader in stem cell transplantation research for neurodegenerative disorders.

The post-mortem study of three cases described in PNAS is the first demonstration that 1) graft survival is indeed attenuated long-term, 2) the grafts undergo degeneration that resembles the pathology observed in Huntington’s disease, and 3) the brain’s inflammatory response could contribute to the compromised survival of grafted cells. The authors also demonstrated that cortical neurons develop Huntington’s disease synapse on the grafts, and may cause neurotoxicity to the healthy cells, inducing grafted neuronal cell death.

Last year, researchers at Rush University Medical Center, USF, and Mount Sinai School of Medicine published research in Nature Medicine showing that grafts in patients with Parkinson’s disease develop Lewy bodies -- a marker of Parkinson’s disease -- after 14 years. Those patients benefited from the grafts for about 12 years, and only about 5 to 8 percent of the transplanted cells had this finding.

“This latest study shows that grafts in patients with Huntington’s disease also undergo disease-specific neuronal degeneration,” said USF's Dr. Freeman, a senior co-author of the study. “However, the neural degeneration in the (genetically unrelated) grafts was even more severe than what was observed in the patient’s own brain. Additionally, clinical benefit, if any, only lasted about two years. These findings may be important to future therapeutic trials of stem cells for the treatment of Parkinson’s and Huntington’s diseases.”

Despite the excitement for cell transplantation therapy using embryonic or stem cells, these results raise concerns for the therapeutic potential of transplantation as a treatment option for Huntington’s disease, the study authors report. However, these observations suggest new potential mechanisms involved in the development of the disease, they conclude. A more in-depth investigation could allow the development of novel therapeutic strategies. The control of the patient’s immune and inflammatory responses holds therapeutic potential and Dr. Cicchetti and colleagues continue their research in that direction.

Dr. Francesca Cicchetti is a professor at the Department of Psychiatry/Neuroscience at Laval University and a researcher in neurobiology. She directs a research laboratory, which focuses on the understanding of neuronal degeneration and the development of treatment strategies for neurodegenerative diseases.

Dr. Thomas B. Freeman is a USF neurosurgeon at Tampa General Hospital, and director of clinical research and medical director of the Center of Excellence for Aging and Brain Repair at the University of South Florida.

This work includes the scientific contribution of the following authors: Samuel Saporta (USF Department of Neurosurgery and Brain Repair), Robert Hauser (Parkinson's Disease and Movement Disorders National Parkinson's Foundation Center of Excellence, USF), Martin Parent (Groupe de recherche sur le système nerveux central (GRSNC)), Martine Saint-Pierre (Centre de Recherche du CHUL (CHUQ)), Paul Sanberg (USF Department of Neurosurgery and Brain Repair), Xiao Li (Emory University School of Medicine), John Parker (University of Louisville Health Sciences Center), Yaping Chu (Rush University Medical Center), Elliot Mufson (Rush University Medical Center), and Jeffrey Kordower (Rush University Medical Center).

David Morgan, PhD

David Morgan, PhD, professor of molecular pharmacology and physiology, was recently named chief scientific officer at the USF Health Byrd Alzheimer’s Institute.

The Byrd Institute this month was legislatively established as a center within USF, and Dr. Morgan will oversee both clinical and basic research at the facility, said Stephen K. Klasko, MD, MBA, CEO for USF Health and the Byrd Institute. A leading neuroscientist in the field of Alzheimer’s research, he will also continue his duties as the director of basic neuroscience research for the College of Medicine.

Dr. Morgan said he plans to work with colleagues at USF Health to make progress on three initiatives over the next year:

• Creating a state-of-the-art center for the diagnosis of Alzheimer’s and other dementias, and using this knowledge to deliver the right drugs to the right patients.

• Building a research team of highly interactive scientists, each of whom works on a different piece of the Alzheimer’s puzzle and understands how to share this expertise with others.

• Starting a patient-dignity initiative that uses students to help patients find their way through the maze of medical offices and procedures and advises patients and families about what to expect during their clinical visits.

Our success will require support from federal, state and private philanthropic sources,” Dr. Morgan said. “We want to create a first-class center for the 21st century that will be ranked among the world’s leading Alzheimer’s research centers – where scientists in our laboratories upstairs can rapidly test their ideas with patients seen in our clinics downstairs.”

Dr. Morgan joined USF in 1992 from the University of Southern California School of Gerontology. He holds a PhD degree in neurobiology from Northwestern University and completed a postdoctoral fellowship in neurogenerontology at USC.

Working with USF colleagues, Dr. Morgan was instrumental in creating a mouse genetically modified to develop Alzheimer’s-like symptoms early in life. Using this Alzheimer’s mouse model, Dr. Morgan’s research focuses on testing therapies that could delay or prevent Alzheimer's disease, determining the role that inflammation plays in the brain, and exploring the development of antibodies to prevent the buildup of beta-amyloid, the substance that clumps into plaques in the brains of Alzheimer's patients. He is a recipient of research grants from the National Institute on Aging and the American Federation of Aging Research. His work has been published in Science, Nature and Journal of Neuroscience.

In other news at the USF Health Byrd Institute:

• Amanda Smith, MD, interim director of the Eric Pfeiffer Suncoast Alzheimer’s and Gerontology Center, is taking on a new role as medical director of the Byrd Institute. She’ll be responsible for the clinical operations there.

• Huntington Potter, PhD, professor of molecular medicine, will continue his work as director of the Alzheimer’s Disease Research Center, a statewide project sponsored by the National Institute on Aging and housed at the Byrd Institute.

• A new board has been formed to advise Dr. Klasko on scientific issues. Dr. Clifton Gooch, MD, professor and chair of neurology, will chair the Byrd Institute Scientific Advisory Board. Other board members are Robert Deschenes, PhD; David Diamond, PhD; Francisco Fernandez, MD; Junius Gonzales, Bruce Lindsey, PhD; Dr. Morgan, Huntington Potter, PhD; Paul Sanberg, DSc, PhD, and Dr. Smith.

Florida Alzheimer’s Disease Research Center studies demonstrate caffeine reverses memory impairment and markedly reduces the hallmark protein for Alzheimer’s disease in the brains and blood of Alzheimer's mice

Tampa, FL (July 6, 2009) -- Coffee drinkers may have another reason to pour that extra cup. When aged mice bred to develop symptoms of Alzheimer’s disease were given caffeine – the equivalent of five cups of coffee a day – their memory impairment was reversed, report University of South Florida researchers at the Florida Alzheimer’s Disease Research Center.

Back-to-back studies published online today in the Journal of Alzheimer’s Disease show caffeine significantly decreased abnormal levels of the protein linked to Alzheimer’s disease, both in the brains and in the blood of mice exhibiting symptoms of the disease. Both studies build upon previous research by the Florida ADRC group showing that caffeine in early adulthood prevented the onset of memory problems in mice bred to develop Alzheimer’s symptoms in old age.

“The new findings provide evidence that caffeine could be a viable ‘treatment’ for established Alzheimer’s disease, and not simply a protective strategy,” said lead author Gary Arendash, PhD, a USF neuroscientist with the Florida ADRC. “That’s important because caffeine is a safe drug for most people, it easily enters the brain, and it appears to directly affect the disease process.”

USF neuroscientist Gary Arendash, PhD, says the preclinical findings suggest caffeine could be a viable treatment for established Alzheimer's.

Based on these promising findings in mice, researchers at the Florida ADRC and Byrd Alzheimer’s Center at USF hope to begin human trials to evaluate whether caffeine can benefit people with mild cognitive impairment or early Alzheimer’s disease, said Huntington Potter, PhD, director of the Florida ADRC and an investigator for the caffeine studies. The research group has already determined that caffeine administered to elderly humans without dementia quickly affects their blood levels of β-amyloid, just as it did in the Alzheimer’s mice.

“These are some of the most promising Alzheimer’s mouse experiments ever done showing that caffeine rapidly reduces beta amyloid protein in the blood, an effect that is mirrored in the brain, and this reduction is linked to cognitive benefit,” Potter said. “Our goal is to obtain the funding needed to translate the therapeutic discoveries in mice into well-designed clinical trials.”

Arendash and his colleagues became interested in caffeine’s potential for treating Alzheimer’s several years ago, after a Portuguese study reported that people with Alzheimer’s had consumed less caffeine over the last 20 years than people without the neurodegenerative disease. Since then, several uncontrolled clinical studies have reported moderate caffeine consumption may protect against memory decline during normal aging. The highly controlled studies using Alzheimer’s mice allowed researchers to isolate the effects of caffeine on memory from other lifestyle factors such as diet and exercise, Arendash said.

Huntington Potter, PhD, director of the Florida Alzheimer's Disease Research Center, says the Byrd Alzheimer's Center at USF hopes to begin clinical trials testing caffeine treatment in people with mild cognitive impairment or early Alzheimer's.

The just-published Florida ADRC study included 55 mice genetically altered to develop memory problems mimicking Alzheimer’s disease as they aged. After behavioral tests confirmed the mice were exhibiting signs of memory impairment at age 18 to 19 months – about age 70 in human years – the researchers gave half the mice caffeine in their drinking water. The other half got plain water.

The Alzheimer’s mice received the equivalent of five 8-oz. cups of regular coffee a day. That’s the same amount of caffeine – 500 milligrams -- as contained in two cups of specialty coffees like Starbucks, or 14 cups of tea, or 20 soft drinks.

At the end of the two-month study, the caffeinated mice performed much better on tests measuring their memory and thinking skills. In fact, their memories were identical to normal aged mice without dementia. The Alzheimer’s mice drinking plain water continued to do poorly on the tests.

Caffeine treatment removed beta amyloid plaques from the brains of the Alzheimer’s mice.

In addition, the brains of the caffeinated mice showed nearly a 50-percent reduction in levels of beta amyloid, a substance forming the sticky clumps of plaques that are a hallmark of Alzheimer’s disease. Other experiments by the same investigators indicate that caffeine appears to restore memory by reducing both enzymes needed to produce beta amyloid. The researchers also suggest that caffeine suppresses inflammatory changes in the brain that lead to an overabundance of beta amyloid.

Since caffeine improved the memory of mice with pre-existing Alzheimer’s, the researchers were curious to know if it might further boost the memory of non-demented (normal) mice administered caffeine from young adulthood through old age. It did not. Control mice given regular drinking water throughout their lives performed as well on behavioral tests in old age as normal mice who received long-term caffeine treatment, Arendash said. “This suggests that caffeine will not increase memory performance above normal levels. Rather, it appears to benefit those destined to develop Alzheimer’s disease.”

Caffeinated Alzheimer's mice performed much better on tests measuring their memory and thinking skills, like finding the submerged platform (circled in photo) in this water maze. Their memories were the same as normal aged mice without dementia.

The researchers do not know if an amount lower than the 500 mg. daily caffeine intake received by the Alzheimer’s mice would be effective, Arendash said. For most individuals, however, this moderate level of caffeine intake poses no adverse health effects, according to both the National Research Council and the National Academy of Sciences. Nonetheless, Arendash said, individuals with high blood pressure or those who are pregnant should limit their daily caffeine intake.

If larger, more rigorous clinical studies confirm that caffeine staves off Alzheimer’s in humans, as it does in mice, this benefit would be substantial, Arendash said. Alzheimer’s disease attacks nearly half of Americans age 85 and older, and Alzheimer’s and other dementias triple healthcare costs for those age 65 and older, according to the Alzheimer’s Association.

In addition to the Florida ADRC, Byrd Alzheimer’s Center and Eric Pfeiffer Suncoast Alzheimer’s and Gerontology Center at USF, researchers from the Bay Pines VA Healthcare System; Saitama Medical University, Saitama, Japan; and Washington University School of Medicine, St. Louis, collaborated on the research. The studies were supported by grants to investigators in the Florida ADRC, a statewide project sponsored by the National Institute on Aging and housed at the University of South Florida’s Byrd Alzheimer’s Center.

Chuanhai Cao, PhD, was lead author of the paper reporting caffeine reduces beta amyloid in the brains and blood of Alzheimer's mice.

Journal articles cited:

1. Caffeine Reverses Cognitive Impairment and Decreases Brain Amyloid-β Levels in Aged Alzheimer’s Disease Mice; Gary W Arendash, Takashi Mori, Chuanhai Cao, Malgorzata Mamcarz, Melissa Runfeldt, Alexander Dickson, Kavon Rezai-Zadeh, Jun Tan, Bruce A Citron, Xiaoyang Lin, Valentina Echeverria, and Huntington Potter; Journal of Alzheimer’s Disease, Volume 17:3 (July 2009).

2. Caffeine Suppresses Amyloid-β Levels in Plasma and Brain of Alzheimer’s Disease Transgenic Mice; Chuanhai Cao, John R Cirrito, Xiaoyang Lin, Lilly Wang, Deborah K Verges, Alexander Dickson, Malgorzata Mamcarz, Chi Zhang, Takashi Mori, Gary W Arendash, David M Holzman, and Huntington Potter; Journal of Alzheimer’s Disease, Volume 17:3 (July 2009).

- About USF Health -

USF Health (www.health.usf.edu) is dedicated to creating a model of health care based on understanding the full spectrum of health. It includes the University of South Florida’s colleges of medicine, nursing, and public health; the schools of biomedical sciences as well as physical therapy & rehabilitation sciences; and the USF Physicians Group. With more than $360 million in research grants and contracts last year, USF is one of the nation’s top 63 public research universities and one of 39 community-engaged, four-year public universities designated by the Carnegie Foundation for the Advancement of Teaching.

- About the Journal of Alzheimer’s Disease -

The Journal of Alzheimer's Disease (http://www.j-alz.com) is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer's disease. The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. Groundbreaking research that has appeared in the journal includes novel therapeutic targets, mechanisms of disease and clinical trial outcomes. The Journal of Alzheimer's Disease has an Impact Factor of 5.101 according to Thomson Reuters' 2008 Journal Citation Reports. The Journal is published by IOS Press (http://www.iospress.nl).