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Toxic plaques of amyloid (red) and tau (brown) tangles are formed on the brain of a mouse whose modeling is at the effect of Alzheimer's disease. One study shows that a DNA-based vaccine reduces both amyloid and tau in the AD model of mice, without unwanted immune responses. Credit: UT Southwestern
A DNA vaccine tested in mice reduces the accumulation of two types of toxic proteins associated with Alzheimer's disease, according to scientific research that could pave the way for a clinical trial.
A new study by Peter O. Donnell Jr. Brain Institute at UT Southwestern shows that a vaccine administered on the skin triggers an immune response that reduces the accumulation of harmful tau and beta-amyloid, without causing brain swelling caused by previous anti-antibody treatments. .
"This study is the culmination of a decade of research that has repeatedly demonstrated that this vaccine can effectively and safely target animal models that we believe are likely to cause disease." Alzheimer's, "said Dr. Roger Rosenberg, founding director of the Center for Alzheimer's Disease at UT. South West. "I think we're about to test this therapy in people."
Research published in Alzheimer's Research and Therapy demonstrates how a vaccine containing DNA encoding a beta-amyloid segment also reduces tau protein in mice modeled for Alzheimer's disease. In addition, the vaccine causes a different immune response that may be safe for humans. Two previous studies from Dr. Rosenberg's lab showed similar immune responses in rabbits and monkeys.
The vaccine is on a short list of promising antibody treatments to protect against the two types of proteins that destroy brain cells when they spread to deadly plaques and entanglements in the brains of patients with Alzheimer's disease.
Although previous research has established that antibodies significantly reduce amyloid accumulation in the brain, Dr. Rosenberg's team needed to find a safe way to introduce them into the body. A vaccine developed elsewhere seemed promising in the early 2000s, but when tested in humans, it caused brain swelling in some patients.
Dr. Rosenberg's idea was to start with the amyloid-encoding DNA and inject it into the skin rather than into muscle to produce a different type of immune response. The injected skin cells form a chain of three beta-amyloid molecules (Aβ42), and the body reacts by producing antibodies that inhibit amyloid formation and, indirectly, tau.
The latest study, consisting of four cohorts of 15 to 24 mice each, shows that the vaccine resulted in a 40% reduction in beta-amyloid and up to 50% in tau protein, with no unwanted immune response. Dr. Rosenberg's team predicts that if amyloid and tau are well the cause of Alzheimer's disease, achieving these reductions in humans could have major therapeutic value.
Drs. Roger Rosenberg, left, and Doris Lambracht-Washington have developed a DNA-based vaccine that can reduce the two toxic proteins associated with Alzheimer's disease in mice. The vaccine was tested on three mammals without an undesirable immune response. Credit: UT Southwestern
"If the onset of the disease could be delayed even five years, it would be huge for patients and their families," said Dr. Doris Lambracht-Washington, lead author of the study. "The number of dementia cases could fall by half."
Alzheimer's disease is characterized by progressive deterioration of the brain as the neurons are destroyed. According to the Center for Disease Control and Prevention, about 5.7 million Americans are suffering from this deadly disease, the number of which is expected to more than double by 2050.
There is no effective treatment, even though several antibodies and other treatments are currently under investigation and clinical trials to target amyloid plaques and entanglements of tau, two features of the disease. One of the strategies, still in clinical benefit testing phase, is to produce antibodies in the laboratory and inject them into the body, a technique called passive immunization.
Dr. Rosenberg said that it would be best to allow the body to produce its own antibodies through active immunization, if this could be done safely. Among the benefits, the vaccine would be more accessible and less expensive. It also produces a wider variety of types of antibodies than preformed antibodies containing only a single specific antibody, Dr. Rosenberg said.
This study is the latest contribution to decades of research on the elimination of toxic proteins in the hope of preventing or slowing the progression of Alzheimer's disease. Scientists have also been trying to develop a method to diagnose the disease at an early stage, so that a revolutionary therapy can be administered before the brain deteriorates.
The field has come a long way this year when scientists from UT Southwestern discovered a "Big Bang" of Alzheimer's disease: the precise point at which a healthy tau molecule becomes harmful without forming any of nodes in the brain.
The findings offer a new strategy for detecting the devastating disease before it develops and has resulted in an effort to develop treatments that stabilize tau proteins before they change. Scientists in southwestern UT are also working on creating a cerebrospinal fluid test capable of detecting an abnormal tau before the onset of symptoms.
Dr. Rosenberg stated that such a test would be an important tool for identifying people undergoing immunization who have not yet experienced symptoms but whose tau and amyloid levels are higher and stored in the brain.
"The longer you wait, the less likely the effect will be," said Dr. Rosenberg. "Once these plates and entanglements are formed, it may be too late."
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DNA vaccine protects against toxic proteins linked to Alzheimer's disease
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