Nov. 13, 2003 In new research, scientists show that two dramatically different approaches may be effective in treating or preventing Alzheimer's disease. One approach involves development of a vaccine that clears deposits of a sticky substance called amyloid beta protein from monkey brains. The amyloid beta protein in monkey brains is the same as that in the brains of Alzheimer's patients, so the hope is that such a vaccine may be effective in humans.
The other research centers on finding out how and to what extent reducing caloric intake can help diminish the pathological symptoms of Alzheimer's disease. Researchers are also working on newer and safer forms of immunization for this devastating disease that afflicts 4.5 million Americans.
Alzheimer's disease is a progressive, degenerative disorder of the brain that results in loss of memory and the ability to think logically and clearly. During its end stages, the brain is littered with dying and dysfunctional neurons, plaques containing the amyloid beta protein, and a profusion of enlarged processes from these neurons. In response to these pathological events, glial cells release proinflammatory proteins involved in nerve cell dysfunction and loss. Although aging is the greatest risk factor for Alzheimer's--its prevalence in the general population doubles every five years after the age of 65--there are a number of other risk factors that might be controlled by changes in lifestyle.
One prominent theory for how Alzheimer's disease develops is that it results from an imbalance in production or clearance of amyloid beta protein, resulting in its accumulation outside of nerve cells to form plaques. As the protein becomes more tightly clumped, it is difficult to clear, diminishing the connections between neurons, and ultimately leading to the dementia associated with Alzheimer's disease.
Several groups are exploring the possibility that vaccines can help the brain in Alzheimer's disease either lower the production of amyloid beta protein or increase its clearance.
Work by Cynthia Lemere, PhD, and her associates at Harvard Medical School shows that vaccinating monkeys with synthetic amyloid beta peptide enhanced the clearance of amyloid beta protein from the brain and into the blood. Although this finding confirms what had already been shown in mice, it is significant because monkeys have the same amyloid beta protein as humans, making them a more natural model for studying clearance of the protein. Dennis Selkoe, co-author, is director and co-founder of Elan, a company that does research and development in neurological disorders such as Alzheimer's disease. The Harvard group's research was not sponsored by Elan.
Over a nine-month period, five aged Caribbean vervet monkeys were given eight injections of the amyloid beta peptide. Five control monkeys did not receive the treatment. All of the immunized monkeys made antibodies to amyloid beta peptide, which were found in blood and, in lower amounts, in cerebrospinal fluid (CSF). Between 22 and 42 days after immunization, levels of amyloid beta protein dropped in the CSF and increased in the blood, suggesting that the antibodies bound to amyloid beta protein and increased its slow release from the CSF to the blood for clearance. In addition, no plaques were found in the immunized animals.
"Our study is the first to show clearance of amyloid beta by vaccination in a primate model," said Lemere, "thus providing further evidence for the potential use of such a vaccine in humans."
Earlier studies that showed mice had increased amyloid clearance after vaccination led to clinical trials to test the treatment in humans. However, the trials were stopped midway because some patients developed cerebral inflammation. While no signs of inflammation were found in any of the immunized monkey brains, Lemere and her team are now attempting an even safer vaccine by developing new amyloid beta compounds.
Investigators at New York University School of Medicine are also working on a safer vaccine. They have altered a portion of the sequence of amyloid beta protein, and preliminary studies show behavioral improvements in mice given the altered amyloid beta, which does not form amyloid fibrils, as does full-length amyloid beta. These amyloid beta derivatives, used in small amounts, result in a lower antibody response than that generated by full-length amyloid beta. A new turn in the research is to determine whether the region of the compound that has been altered is important for lessening the potentially toxic inflammatory autoimmune response, and thus contributing to a safer vaccine.
"Our work shows that relatively low levels of circulating antibodies to amyloid beta may benefit Alzheimer's disease patients," said NYU's Einar Sigurdsson, PhD. "Use of amyloid beta derivatives can potentially reduce the toxicity associated with the full-length native amyloid beta vaccine."
These investigators are now working on a new memory test for mice and on characterizing the antibodies generated toward the vaccines. They hope that together these studies will help show if any particular properties of the antibodies correlate with cognitive improvement.
In other work, researchers at the National Institute for Longevity Sciences in Japan have developed a new oral vaccine for Alzheimer's disease in mice using adeno-associated virus vector. The advantage of an oral vaccine is that it will not result in a potentially toxic autoimmune response. The group, led by Hideo Hara, PhD, plans next to give the vaccine to aged monkeys to test its effectiveness in primates.
On a different front, other researchers are looking at a change-in-lifestyle approach to preventing Alzheimer's disease. While trying to identify factors that contribute to aging and thereby might contribute to the development of Alzheimer's disease, Todd Morgan, PhD, Caleb Finch, PhD, and other colleagues at the University of Southern California, Los Angeles, used a remarkably effective and simple means of delaying aging: caloric restriction.
By reducing food intake by 10 to 40 percent in experimental animals, inflammatory changes are suppressed in the aging brain and other tissues. In collaboration with David Morgan and his colleagues at the University of Southern Florida in Tampa, the two research teams showed that six weeks of caloric restriction reduced the glial inflammatory response as well as the number of amyloid beta plaques in a transgenic experimental animal model of Alzheimer's disease.
The researchers examined the effects of caloric restriction in two different lines of transgenic mice that are bioengineered to express either mutated human amyloid beta precursor protein alone or in combination with mutated presenilin1. Mutations in these two genes are responsible for causing inherited forms of Alzheimer's disease in humans. Mouse brains from both groups showed decreased amyloid beta deposits and decreased glial inflammation.
"These ameliorating influences of caloric restriction on development of amyloid plaques and inflammation in these transgenic mice are consistent with clinical reports that people with high calorie diets are at increased risk for developing Alzheimer's disease," said Morgan. "These results suggest that dietary changes, even in adulthood, may be an approach to prevention and treatment of Alzheimer's disease."
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