Use of an active DNA vaccine in mice with hallmarks of Alzheimer’s disease significantly lowered the toxic accumulation of amyloid plaques and tau without triggering severe brain swelling — a damaging complication seen in earlier antibody treatments.
These results may pave the way to test this DNA vaccine in clinical trials, researchers said.
Immunotherapy – the treatment of disease by utilizing the immune system – has potential as an Alzheimer’s treatment. However, current assessments of amyloid-beta (Aβ) immunotherapy in preventing this disease in several completed and ongoing trials show inconsistent responses.
Notably, the first active anti-Aβ peptide clinical trial of a DNA amyloid-beta peptide 1–42 (Aβ42) vaccine in Alzheimer’s patients led to encephalitis – inflammation of the brain that causes mild to life-threatening symptoms.
Of note, Aβ42 is one of the forms that amyloid-beta peptide fragments — those that accumulate in a patient’s brain — can assume. These are mainly found in amyloid plaques and correlate with disease status.
To avoid complications like autoimmune inflammation and encephalitis, many ongoing clinical trials are now utilizing passive vaccination with mouse or human antibodies against amyloid-beta protein. Passive vaccination is the direct application of antibodies, instead of introducing an antigen (a toxin, protein, or foreign substance which induces an immune response) that the body naturally reacts to and creates its own antibodies.
A recent study using a passive vaccine of mouse antibodies targeting amyloid beta protein showed promising results in reducing a toxic buildup of amyloid plaques and protecting against cognitive decline. But passive immunization is not an ideal approach for immunotherapy because it is neither long-lasting nor cost-effective.
Active immunization – the induction of antibody production by a patient’s own immune system – can be achieved by two methods: via the administration of an antigen directly, or through DNA vaccination in which the DNA encodes the antigen.
In DNA vaccination, DNA is injected into the skin where antigens are made, and then are taken up by dendritic cells – a type of immune cells that present antigens to the immune system – traveling to the resident lymph nodes, where robust immune responses can be generated. These dendritic cells then present the antigen to B- and T-cells for antibody production and, ultimately, immunization.
Researchers from UT Southwestern’s Peter O’Donnell Jr. Brain Institute had previously shown that the use of a specific DNA vaccine against amyloid-beta protein, known as a DNA Aβ42 trimer, is non-inflammatory and induces an immune response that effectively removes amyloid-beta from the brain in a mouse model of Alzheimer’s.
Besides amyloid-beta plaque accumulation, however, the aggregation and spread of another protein, called tau, is also associated with progression of Alzheimer’s. This protein was not accounted for in their previous study.
Researchers now tested if the DNA Aβ42 trimer vaccine was effective in a mouse model that exhibits both amyloid-beta and tau pathologies characteristic of the human disease.
The vaccine prompted a 40 percent reduction in amyloid-beta and up to a 50 percent reduction in tau accumulation in the mouse brain. Importantly, it did not induce autoimmune inflammation and encephalitis as found in the clinical trial using active Aβ42 peptide immunization in patients with Alzheimer’s disease.
“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,” Roger Rosenberg, founding director of the Alzheimer’s Disease Center at UT Southwestern, said in a press release. “I believe we’re getting close to testing this therapy in people.”
The researchers hypothesize that if amyloid and tau are in fact the cause of Alzheimer’s disease, achieving such 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 Doris Lambracht-Washington, the study’s senior author. “The number of dementia cases could drop by half.”
The vaccine was also able to reverse a signaling pathway that is altered in Alzheimer’s disease, called MAPK signaling, that is thought to play a role in tau modification and toxic accumulation.
Efforts are underway to develop a test that can detect abnormal tau before symptoms arise, a potential important tool in identifying 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,” Rosenberg said. “Once those plaques and tangles have formed, it may be too late.”
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