The brain under the magnifying glass: how IBioBA seeks answers to understand and challenge Alzheimer’s disease

In the framework of World Alzheimer’s Day, we share the work carried out by IBioBA to understand the disease, providing knowledge to understand the functioning of the brain and the development of therapeutic strategies. A sample of the importance of promoting scientific research to solve health problems affecting the population.

It is very likely that whoever reads this text knows someone, first or second hand, diagnosed with Alzheimer’s, a brain disorder that slowly affects memory, the ability to think and reason, and the ability to perform simple tasks. According to the World Health Organization, dementia is the result of various diseases and injuries that affect the brain and affects more than 55 million people around the world. Alzheimer’s disease is the most common form of dementia and may account for 60% to 70% of cases.

The disease worsens over time: it mainly affects older people, but not everyone will get it as they get older. Alzheimer’s is not something to be expected in the normal aging process, but is the result of complex changes in the brain that begin long before the symptoms and result in the loss of neurons and their connections. And although the disease was discovered in 1906, the causes of its emergence are still not fully understood.

Tomás Falzone and his group “Cellular and genetic neurobiology” are working along these lines, with the aim of understanding the molecular and cellular mechanisms involved in this disease. “In the laboratory we approach the disease in two ways: on the one hand, trying to understand how the nervous system works, to be able to compare it with how it works when there is disease. And on the other, by generating disease modeling: knowing what we want to see and the pathologies or defects associated with neuronal malfunction. To do this, we generate neuronal cultures from patients’ cells and develop brain organoids – a three-dimensional neural tissue structure – that we use to study the effect of transport defects and oxidative stress in Alzheimer’s disease”, explains the researcher.

Falzone’s laboratory specializes precisely in the study of axonal transport, a kind of highway system between neurons that allows the movement of molecules and substances between the body of the cell (soma) and its more distant parts, such as the dendrites and the axon. Knowing this mechanism is essential to understand how neurons stay healthy and how they communicate information: “We study this process because it has been shown that it is altered in neurodegenerative diseases”, he says.

Mariana Holubiec is a researcher in Falzone’s team and last year led a study published in the journal Free Radical Biology & Medicine in which they evaluated the state of neuronal oxidation and discovered that organoids with the APP (amyloid precursor protein) mutation have a higher state of oxidation. APP is known to be the precursor of a peptide that is the main component of amyloid plaques, one of the two pathological hallmarks present in the brain tissue of people with Alzheimer’s disease (the other hallmark is neurofibrillary tangles, generated from the accumulation of tau protein).

“We studied what happens to organoids with the disease and have seen that they suffer from different oxidative stress than control organoids. Their mitochondrial functioning energy reserve is also diminished. Because the dynamics are impaired, they are more vulnerable to oxidative changes”, Falzone explains. These studies give them the guideline of how, for example, the same ‘stress of living’ could affect a healthy person and another who has functional damage: “these people will find it more difficult to age well”, he adds.

The generation of human neuronal tissue models (brain organoids) that recapitulate basic aspects of Alzheimer’s disease are very relevant to determine whether the defective cellular processes that lead to the disease are independent or not of the accumulation of pathology and can be used in the testing of reparative strategies.

On the other hand, they have seen that removing tau changes the dynamics of axonal transport and electrical activity. “In the disease there is a phenomenon of neuronal hyper-excitability (high electrical activity, which generates an imbalance in brain functioning) and, by reducing the tau protein as a therapeutic strategy, excitability can be reduced. The challenge now, on which we are working in collaboration with Dr. Elena Avale, is to improve the genetic correction tools to reduce tau only in hyper-excited neurons and not in all of them”, explains Tomás in reference to the challenges for the future.

Another of the laboratory’s projects, aimed at generating local disease models, is being carried out together with colleagues from the Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI, CONICET) and neurologists from the Favaloro Hospital, with whom they are assembling the first biobank of cells from patients with neurodegenerative diseases, mainly primary tauopathies. This is very relevant since it will allow them to generate models from Argentine patients to study these diseases in depth, and to develop diagnostic and testing strategies for possible therapeutic tools.