A DNA Vaccine Reduces Both Amyloid-β and Tau Aggregates in Mice

Alzheimer's disease begins with increasing amounts of amyloid-β in the brain, leading to solid aggregates that distort cell function and cause a comparatively mild level of cognitive impairment. Over time, this initial abnormal biochemistry sets the stage for the later, much more serious accumulation of an altered form of tau protein. Tau aggregates causes severe loss of function and cell death, with dementia as the result. The research community is divided over the deeper origins of Alzheimer's, the processes that cause only some people to exhibit raised levels of amyloid-β, but it seems clear that comprehensive, effective treatment strategies must in some way tackle both amyloid and tau aggregates. If one therapy can clear out both forms of aggregate, then all to the good, but unfortunately there are few examples capable of this outcome.

In the case here, the reduction in amyloid-β is achieved directly, while the reduction in tau is achieved indirectly. The particular form of amyloid-β targeted by the therapy is involved in altering tau in ways that encourage its aggregation. Whether this mechanism is important in humans to the same degree that it is important in the particular animal model used here is a question best resolved by moving to human trials. One of the challenges inherent in Alzheimer's disease research is that humans are one of the only species to exhibit anything even remotely resembling the condition. Thus the mice used for testing are altered in highly artificial ways to produce models of Alzheimer's. The fine details of how the models differ from human Alzheimer's biochemistry are of great importance, and one of the reasons for the lengthy catalog of failure in clinical trials over the past few decades.

A DNA vaccine tested in mice reduces accumulation of both types of toxic proteins associated with Alzheimer's disease. The vaccine is delivered to the skin, prompting 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. I believe we're getting close to testing this therapy in people."

Although earlier research established that antibodies significantly reduce amyloid buildup in the brain, researchers 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. The new 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. If amyloid and tau are indeed the cause of Alzheimer's disease, achieving these reductions in humans could have major therapeutic value. 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.

Link: https://www.utsouthwestern.edu/newsroom/articles/year-2018/dna-vaccine-alzheimers.html

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