Researchers at the University of Texas (UT) Southwestern Medical Center reported Tuesday that they have developed a vaccine that could arm the body to attack Alzheimer's plaques and tangles before they even start to shut down the brain. They hope to begin testing the vaccines in humans soon.
Their new vaccine for the first time has targeted both amyloid-containing plaques and tau—both considered hallmarks for a definitive identification of Alzheimer’s disease—in a mouse with the disease.
The shot uses DNA from Alzheimer's proteins to teach the immune system to fight these compounds and keep them from accumulating in the brain. Researchers say their new Alzheimer's vaccine—so-called DNA Aβ42—could conceivably cut the number of dementia cases in half.
The new vaccine—unlike a previous attempt that caused swelling in the brain when DNA was injected into the test mice's muscles—is administered by injecting it superficially into the skin. The injected skin cells then make a three-molecule chain of beta-amyloid, and the body responds by producing antibodies that ward off the build-up of amyloid and tau.
“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,” wrote lead author, Roger N. Rosenberg, founding director of the National Institutes of Health (NIH) funded Alzheimer’s Disease Center at UT Southwestern Department of Neurology and Neurotherapeutics. Co-authors include Min Fu and Doris Lambracht-Washington also of UT Southwestern Medical Center in Dallas, Texas. The researchers published their findings in the journal, Alzheimer’s & Research Therapy, a BMC-series journal publication.
As researchers do not currently know precisely when amyloid and tau begin to form, Rosenberg said physicians would determine when to administer the vaccine by conducting amyloid and tau PET brain scans.
Though Rosenberg’s research has nothing to do with that of Rudolph Tanzi, the Harvard scientist who co-discovered all three familial early-onset Alzheimer’s disease genes and leads the Cure Alzheimer’s Fund's Alzheimer’s Genome Project, their premises are similar. Keep amyloid low. Avoid Alzheimer’s.
Tanzi’s lab at Massachusetts General Hospital (MGH) are mapping the microbiome of the brain—the population of microorganisms, some helpful and some pathological, that exists inside the brain—utilizing autopsied brain samples that tested positive for Alzheimer’s disease pathology. Researchers with The Brain Microbiome Project are looking for the most common germs found in the brain to attempt to determine which ones ultimately lead to Alzheimer’s disease. With the information, they hope to develop therapeutics for preventing and treating the disease.
That’s aside from the three-dimensional human stem cell-derived neural culture system (or simulated human brain organoid), “Alzheimer’s-in-a-Dish,” that Tanzi and colleague Dr. Doo Yeon Kim created with Alzheimer’s genes. That system essentially replays the Alzheimer’s disease plaque and tangle processes. Using the system, Tanzi developed a drug for Alzheimer’s disease including gamma secretase modulators and metal chaperones to lower beta-amyloid and tangle burden in the brain.
Though the research is incredibly complex, scientists used stem cells to create human nerve cells. They then put them in a gel to simulate the human brain, and thus created full blown Alzheimer’s pathology in a Petri dish allowing them to have the first real view of the events that typically happen over decades—the formation of amyloid plaques that then lead to tangles and inflammation—in the brain, he said.
Alzheimer’s-in-a-Dish solved the decades-old argument of whether the amyloid plaques or the tangles are to blame for Alzheimer’s disease, Tanzi said. “There is not a debate anymore,” he said. “All data say that if you keep the amyloid low, than you stop Alzheimer’s.”
Similar to Rosenberg’s quest to stop Alzheimer’s before it starts, Tanzi likens the need for early intervention and treatment of dementia to cancer and heart disease. “Unlike with heart disease and cancer, we don’t diagnose and treat Alzheimer’s disease until the symptoms hit, and then we treat the cause, the amyloid plaques. We needed to stop the amyloid plaques 10 to 20 years before the person shows symptoms.”
Tanzi said we can now determine the possibility of a person getting Alzheimer’s later in life using brain imaging and biomarkers when they are still asymptomatic, just like doctors do with cholesterol tests for heart disease. He said the time is not far in the future where blood tests will be available for Alzheimer’s as well.
In the same way Americans now take a drug to prevent the buildup of cholesterol, Tanzi hopes that in the near future they will take one to bring their brain amyloid protein levels down. “Someday, once we have an effective and safe anti-amyloid drug, everyone will have their amyloid checked by 50 years old, let’s say, like they do with a colonoscopy. If you have a higher than normal amount, you can take a drug to prevent Alzheimer’s symptoms of dementia from occuring. By 2025, I think we’ll be there. If all goes swimmingly well, a GSM can be available in as little as five years.”
Or maybe they’ll just get Rosenberg’s vaccine.
“We report, for the first time in an AD mouse model, that active DNA Aβ42 immunization into the skin targets two pathologies: amyloid-containing plaques and tau,” researchers from UT wrote in their study. “DNA vaccination, in which not the antigen (peptide or protein) but the DNA encoding this peptide is administered, is an alternative route of vaccination. Genes encoded by the DNA are expressed within the skin, and the peptides are taken up by dendritic cells traveling to the regional lymph nodes and presenting the antigen to B and T cells.”
The researchers at UT Southwestern Medical Center have already shown that full-length DNA Aβ42 trimer immunization is non-inflammatory and induces measurable immune response “DNA Aβ42 trimer immunization has been shown to be effective in removing amyloid from the brain in immunized double-transgenic mice,” the researchers wrote.” Now they have found that immunotherapy with DNA Aβ42 trimer leads to reduction of amyloid peptides and amyloid plaques as well as “…for the first time that DNA Aβ42 trimer immunization leads also to significant reduction of tau from the mouse brain.”
A neurodegenerative disorder, Alzheimer’s disease is the most common form of dementia found in the aging population. Rosenberg and others have contended for years that immunotherapy targeting amyloid beta (Aβ) build-up in the brain may provide a possible treatment option and may help prevent the disease from progressing. A number of immunization approaches have been fruitless, including one that was stopped after researchers noted the development of autoimmune encephalitis in 6% of their patients.
Today, Alzheimer’s disease is the 6th leading cause of death in the United States. It cripples the brains of those who have it as they age as beta-amyloid proteins in the brain get stuck together and form tangles of tau proteins inhibiting neural connections. There is no cure and to date only symptomatic treatment options are available.
The pathologic features of amyloid plaques and neurofibrillary tangles are considered hallmarks for a definitive identification of Alzheimer’s disease. And the origin and development of the disease has been strongly associated with the accumulation and clustering of amyloid beta in the brain. Nearly 30 years ago the amyloid cascade hypothesis was formulated, which postulated that amyloid deposition is the initial event leading to Alzheimer’s.
Injected into the skin, Rosenberg's vaccine has shown to trigger the skin cells to produce a three-molecule chain of beta-amyloid. Anticipating the Alzheimer’s plaques and tangles before they form, the immune system is then activated to produce antibodies to fight beta-amyloid and tau proteins.
The research at UT Southwestern Medical Center tested four groups of mice. Some 40% of beta-amyloid plaques were reduced in vaccinated mice, and as much as 50% of their tau tangles diminished. Researchers said they observed no adverse immune response with the vaccine. The result, say researchers, show that with the vaccine, the body is armed and ready to attack the Alzheimer's plaques and tangles before they start to shut down the brain.
Scientists throughout the U.S. are going to great lengths to develop treatments for dementia. In an article featured in Elsevier’s Alzheimer's & Dementia: Translational Research & Clinical Interventions, Jeffrey Cummings, of Cleveland Clinic’s Lou Ruvo Center for Brain Health reports that there were, as of January 2018, 112 agents in the Alzheimer’s disease treatment pipeline. Of these, Cummings reports, “63% are disease-modifying therapies, 22% are symptomatic cognitive enhancers, and 12% are symptomatic agents addressing neuropsychiatric and behavioral changes.” (Cummings review is based on clinical trial activity as recorded in clinicaltrials.gov, a comprehensive US government database. Federal law requires that all clinical trials conducted in the United States be registered on the site.) And the Alzheimer’s disease drug development pipeline is larger this year than it was in 2017.
