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DNA Vaccine Reduces Both Toxic Proteins Linked to Alzheimer’s

Summary: A new DNA vaccine tested in mice significantly reduces tau and amyloid beta, two proteins implicated in Alzheimer’s disease. The findings, researchers say, may pave the way for clinical trials in humans with the neurodegenerative disease.

Source: UT Southwestern Medical Center.

A DNA vaccine tested in mice reduces accumulation of both types of toxic proteins associated with Alzheimer’s disease, according to research that scientists say may pave the way to a clinical trial.

A new study by UT Southwestern’s Peter O’Donnell Jr. Brain Institute shows that a vaccine delivered to the skin prompts an immune response that reduces buildup of harmful tau and beta-amyloid – without triggering severe brain swelling that earlier antibody treatments caused in some patients.

“This study is the culmination of a decade of research that has repeatedly demonstrated that this vaccine can effectively and safely target in animal models what we think may cause Alzheimer’s disease,” said Dr. Roger Rosenberg, founding Director of the Alzheimer’s Disease Center at UT Southwestern. “I believe we’re getting close to testing this therapy in people.”

The research published in Alzheimer’s Research and Therapy demonstrates how a vaccine containing DNA coding for a segment of beta-amyloid also reduces tau in mice modeled to have Alzheimer’s disease. In addition, the vaccine elicits 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 shortlist of promising antibody treatments aimed at protecting against both types of proteins that kill brain cells as they spread in deadly plaques and tangles on the brains of Alzheimer’s disease patients.

Although earlier research established that antibodies significantly reduce amyloid buildup in the brain, Dr. Rosenberg’s team needed to find a safe way to introduce them into the body. A vaccine developed elsewhere showed promise in the early 2000s, but when tested in humans, it caused brain swelling in some patients.

Dr. Rosenberg’s idea was to start with DNA coding for amyloid and inject it into the skin rather than the muscle to produce a different kind of immune response. The injected skin cells make a three-molecule chain of beta-amyloid (Aβ42), and the body responds by producing antibodies that inhibit the buildup of amyloid and indirectly also of tau.

The latest study – consisting of four cohorts of between 15 and 24 mice each – shows the vaccine prompted a 40 percent reduction in beta-amyloid and up to a 50 percent reduction in tau, with no adverse immune response. Dr. Rosenberg’s team predicts that if amyloid and tau are indeed the cause of Alzheimer’s disease, achieving these reductions in humans could have major therapeutic value.

“If the onset of the disease could be delayed by even five years, that would be enormous for the patients and their families,” said Dr. Doris Lambracht-Washington, the study’s senior author. “The number of dementia cases could drop by half.”

Alzheimer’s disease is characterized by progressive deterioration of the brain as neurons are destroyed. About 5.7 million Americans have the fatal disease, with the number expected to more than double by 2050, according to the Centers for Disease Control and Prevention.

No effective treatment exists, though several antibody and other therapies are being researched and tested in clinical trials to target amyloid plaques and tau tangles – both hallmarks of the disease. One strategy, still being tested for clinical benefits, involves producing the antibodies in the laboratory and injecting them into the body – a technique referred to as passive immunization.

Dr. Rosenberg said allowing the body to produce its own antibodies through active immunization would be the preferable strategy, if it can be done safely. Among the advantages, the vaccine would be more accessible and less expensive. It also produces a wider variety of antibody types than the preformed antibodies containing only one specific antibody, Dr. Rosenberg said.

The study is the latest contribution to decades of research focusing on clearing toxic proteins in hopes of preventing or slowing the progression of Alzheimer’s disease. Scientists have also been trying to develop a method of diagnosing the condition at its earliest stage so that a future breakthrough therapy could be given before the brain deteriorates.

The field advanced significantly earlier this year when UT Southwestern scientists discovered a “Big Bang” of Alzheimer’s disease – the precise point at which a healthy tau molecule becomes harmful but has not yet formed tangles in the brain.

amyloid beta

Toxic amyloid plaques (red) and tau tangles (brown) form on the brain of a mouse modeled to have Alzheimer’s disease. A study shows a DNA vaccine reduces both amyloid and tau in the mouse AD model, with no adverse immune responses. NeuroscienceNews.com image is credited to UT Southwestern.

The findings offer a new strategy to detect the devastating disease before it takes hold and has spawned an effort to develop treatments that stabilize tau proteins before they shift shape. UT Southwestern scientists are also working to create a spinal fluid test that can detect abnormal tau before symptoms arise.

Dr. Rosenberg said such a test would be an important tool to identify people for vaccine treatment who have not yet shown symptoms but have higher levels of tau and amyloid stored in the brain.

“The longer you wait, the less effect it will probably have,” Dr. Rosenberg said. “Once those plaques and tangles have formed, it may be too late.”

About this neuroscience research article

Dr. Rosenberg is a Professor of Physiology and Neurology & Neurotherapeutics. He holds the Abe (Brunky), Morris and William Zale Distinguished Chair in Neurology.

Dr. Lambracht-Washington is an Assistant Professor of Neurology & Neurotherapeutics. She presented the preliminary findings on tau reduction in mice in 2016 at the Alzheimer’s Association International Conference and was awarded a grant by the UT Southwestern Circle of Friends to continue the research. Min Fu, a Research Scientist at UTSW, collaborated on the study.

Funding: The research was also supported by the National Institutes of Health; the Zale Foundation; the Rudman Foundation; the Presbyterian Village North Foundation; Freiberger, Losinger, and Denker Family Funds; Triumph Over Alzheimer’s; and AWARE.

Source: James Beltran – UT Southwestern Medical Center
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to UT Southwestern.
Original Research: Open access research for “Active full-length DNA Aβ42 immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology” by Roger N. Rosenberg, Min Fu and Doris Lambracht-Washington in Alzheimer’s Research and Therapy. Published November 20 2018.
doi:10.1186/s13195-018-0441-4

Cite This NeuroscienceNews.com Article
UT Southwestern Medical Center”DNA Vaccine Reduces Both Toxic Proteins Linked to Alzheimer’s.” NeuroscienceNews. NeuroscienceNews, 21 November 2018.
<http://neurosciencenews.com/dna-vaccine-alzheimers-10241/>.
UT Southwestern Medical Center(2018, November 21). DNA Vaccine Reduces Both Toxic Proteins Linked to Alzheimer’s. NeuroscienceNews. Retrieved November 21, 2018 from http://neurosciencenews.com/dna-vaccine-alzheimers-10241/
UT Southwestern Medical Center”DNA Vaccine Reduces Both Toxic Proteins Linked to Alzheimer’s.” http://neurosciencenews.com/dna-vaccine-alzheimers-10241/ (accessed November 21, 2018).

Abstract

Active full-length DNA Aβ42 immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology

Background
Alzheimer’s disease (AD) is the most well-known and most common type of age-related dementia. Amyloid deposition and hyperphosphorylation of tau protein are both pathological hallmarks of AD. Using a triple-transgenic mouse model (3xTg-AD) that develops plaques and tangles in the brain similar to human AD, we provide evidence that active full-length DNA amyloid-β peptide 1–42 (Aβ42) trimer immunization leads to reduction of both amyloid and tau aggregation and accumulation.

Methods
Immune responses were monitored by enzyme-linked immunosorbent assay (ELISA) (antibody production) and enzyme-linked immunospot (cellular activation, cytokine production). Brains from 20-month-old 3x Tg-AD mice that had received DNA Aβ42 immunotherapy were compared with brains from age- and gender-matched transgenic Aβ42 peptide-immunized and control mice by histology, Western blot analysis, and ELISA. Protein kinase activation and kinase levels were studied in Western blots from mouse hemibrain lysates.

Results
Quantitative ELISA showed a 40% reduction of Aβ42 peptide and a 25–50% reduction of total tau and different phosphorylated tau molecules in the DNA Aβ42 trimer-immunized 3xTg-AD mice compared with nonimmunized 3xTg-AD control animals. Plaque and Aβ peptide reductions in the brain were due to the anti-Aβ antibodies generated following the immunizations. Reductions of tau were likely due to indirect actions such as less Aβ in the brain resulting in less tau kinase activation.

Conclusions
The significance of these findings is that DNA Aβ42 trimer immunotherapy targets two major pathologies in AD—amyloid plaques and neurofibrillary tangles—in one vaccine without inducing inflammatory T-cell responses, which carry the danger of autoimmune inflammation, as found in a clinical trial using active Aβ42 peptide immunization in patients with AD (AN1792).

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