For over 20 years, Dr. Ferreira has been leading a research group aimed at investigating the role of beta-amyloid oligomers in AD. “Since they were described as possible toxins in AD, 24 years ago, more than 5,000 scientific articles show the possible negative impacts of these oligomers on the functioning of brain synapses, and many of these papers came from our group. Since the beginning of the 2000s, we have studied this topic”, he informs. He explains that beta-amyloid plaques may not be so important for AD because they accumulate in specific areas, while the oligomers are soluble and circulate in the cerebrospinal fluid, and, since they are smaller, bind to neurons, damaging synapses in several parts of the brain, which would cause further memory loss and mental confusion.
“It is believed today that plaques are a kind of a garbage dump, a place where the brain accumulates that toxic protein to minimize the problem. On the edge of this ‘dump’ you will have problems, but not far from it. Oligomers, on the other hand, would be like small garbage bags, they are soluble and dissolve in the cerebrospinal fluid, and they wander around the brain attacking the synapses. For example, it is as if the plates were a sanitary landfill and the oligomers the scattered garbage on the streets, and the latter, yes, will block sewers and cause flooding”, facilitates the scientist.
Interested in a way of targeting these oligomers alone, the authors of the article used an artificial mini antibody, which was developed in 2017, in a scientific collaboration of the group in another study. “This started years ago, with Dr. Adriano Sebollela, in a collaboration between Northwestern University, in the USA, USP Ribeirão Preto, and UFRJ. He identified natural antibodies that preferentially bind to oligomers. From there, he sequenced the DNA that gives rise to the antibody, and we took the little piece of the genetic sequence responsible for the recognition of this oligomer to use it for the creation of the artificial antibody, the NUsc1”, he recalls.
But the way of applying these antibodies did not favor their clinical use, as it would be necessary to perform periodic injections in the patient’s cerebrospinal fluid. “That’s when we thought, ‘What if we could teach our neurons to produce this molecule?’ So, we put the NUsc1 DNA genetic sequence in an attenuated viral vector capable of infecting neurons, but which, instead of causing disease, causes the neuron to start producing that molecule. It’s gene therapy. We’re modifying the cell’s genetics so that it produces something it couldn’t produce before. In this case, we are teaching the neuron to produce an artificial and tiny antibody, incapable of causing neural inflammation”.
The study was performed in mice with AD. The viral vector was injected only once, and it was observed that the rodent neurons began to produce NUsc1. The results were also as expected: the proliferation of antibodies reduced memory impairment induced by beta-amyloid oligomers and, notably, reversed memory deficits in mice, a result of potential relevance for the scientific community and for people affected by Alzheimer’s Disease.
When asked about the future of this discovery, Dr. Sérgio seemed hopeful, however, informed us that there is still a lot of research and tests to be done. “An important next step would be to get partnerships in the biopharmaceutical industry to optimize the delivery and to apply it in a future clinical trial. We started this research more than seven years ago, and at the time this viral vector was the best we had. Today there are already better vectors. Instead of injecting the virus into the patient’s brain, perhaps we could do it through the blood, which would be less invasive, and the virus would reach the brain through the blood-brain barrier. But, before even thinking about trials with people, we would need to test in animal models closer to humans, such as other primates, to better understand the safety. It would be a big leap to jump from the effects observed in the brains of mice straight to a research involving human beings”, clarifies the researcher.
Even though it is still very inceptive to be considered a future therapy, the new discovery is, at the very least, optimistic for the diagnosed people, their families, and caregivers who live with AD, especially when for more than 100 years there has been a lack of efficient drugs with little adverse risks to patients.