Study associates schizophrenia with vascular changes in the brain

Study published in Journal of Molecular Psychiatry suggests that schizophrenia may be related to alterations in the vasculature of some regions of the brain. In their work, researchers from Unicamp (Campinas State University), D’Or Institute of Research and Teaching (Idor) and UFRJ (Federal University of Rio de Janeiro) observed that neural cells (astrocytes) derived from patients with the disease induce the formation of a greater number of vessels, only the thinnest ones, which can affect the vascular network of some brain areas.

Schizophrenia is considered a serious and multifactorial mental disorder, affecting up to 1% of the world’s population. Common symptoms include loss of contact with reality (psychosis), hallucinations (hearing voices, for example), false beliefs (delusions), abnormal thinking and behavior, decreased motivation, and worsening mental (cognitive) function.

In the study, the researchers focused on the role of astrocytes – cells essential for the maintenance of neurons and which function as energy plants in the central nervous system – in the development of the disease. In addition to indicating new therapeutic targets, the study advances the understanding of the molecular mechanisms of the disease.

“We have shown that astrocytes can be involved with a change in the thickness of the cerebral vessels. And this may be related to a major factor in schizophrenia: decreased metabolic flux [produção de energia] in certain regions of the brain. “This reinforces the role of astrocytes as a central element of the disease, making them a target for new therapies,” explains Daniel Martins-de-Souza, professor at the Institute of Biology of the State University of Campinas (IB-Unicamp). and one of the authors of the article.

The work was supported by Fapesp through a thematic project and a postdoctoral fellowship granted to Juliana Minardi Nascimento, first author of the article, together with Pablo Trindade, of UFRJ and Idor.

Alteration of the vascularization

The researchers compared astrocytes derived from skin cells from patients with schizophrenia to those from people without the condition. This part of the study was conducted in the laboratory of Stevens Rehen, a researcher at Idor and a professor at the UFRJ Institute of Biology.

To do so, the team reprogrammed skin cells from schizophrenia patients and those in the control group to regress to a pluripotent stage characteristic of stem cells (induced pluripotent stem cells, or iPSCs). He then induced cell differentiation and transformed iPSCs into neural stem cells (which can give rise to both neurons and astrocytes).

“Previous studies had already suggested that both molecular and functional abnormalities of astrocytes might be involved in the pathogenesis of schizophrenia. In our work, we confirmed this relationship on the basis of studies with induced pluripotent stem cells. As we did,” explains Martins-de -Souza.

With patient-derived astrocytes and healthy controls, the researchers performed two tests. Firstly, a proteomic analysis (which identifies the set of proteins present in the sample) was carried out at the Unicamp Neuroproteomics Laboratory, to verify the variation of the proteins expressed in the control cells and in those of the patients with schizophrenia.

“When we evaluated the proteomics of cells with schizophrenia, we observed immune alterations associated with astrocytes. We also found differences in inflammatory cytokines and several other proteins indicating an angiogenic action. [que favorece o crescimento de novos vasos] in the cerebral vasculature”, informs Nascimento.

After proteomic analysis, the researchers performed functional tests. It was observed that the inflammatory response of the astrocytes in the patients was altered and that the substances released by them affected the vascular supply. Running these tests was part of Trindade’s postdoctoral studies.

For this, the researchers used a model of the vasculature based on the membrane surrounding the chick embryo. Known as CAM (English acronym for the embryonic chorioallantoic membrane of chicken eggs), the methodology has been used to study the effect of substances on tissue vascularization.

This process was conducted by collaborators at the Universidad de Chile. “Basically, we placed the conditioned medium of the astrocytes, with all the substances that these cells secrete, within the vascular region of the fertilized eggs. As the vascular cells multiply, it is possible to see how the vessels form. Thus, it can be observed whether substances secreted by cultured cells induce or inhibit egg vascularization,” says Trindade.

In addition to modifying the vasculature, astrocytes derived from patients with schizophrenia exhibited a profile of chronic inflammation. “Astrocytes are known to be neural cells that have the role of regulating the immune response in the region. Thus, it is possible that they promote more immature or less efficient vascularization. We found that, compared to the control group, patient-derived astrocytes secrete a higher amount of interleukin-8, a signal of inflammation and suspected to be the main agent of schizophrenia-associated vascular dysfunction,” explains the researcher at FAPESP. .

The authors say the findings reinforce the role of neurodevelopment in schizophrenia, which, by all indications, is mediated by astrocytes.

“The symptoms of the disease usually appear when you are a young adult. But, as we have shown in the work, the glial cells in these patients are different from the start, which interferes with neurodevelopment in the uterus as well. Differentiation and occurs therefore the formation of the brain It may therefore be that, during the maturation of the brain, events such as the one we verified in the study take place: a systematically altered vascularization, which leads to the malformation of the brain circuits that can trigger schizophrenia in adulthood “, says Nascimento .

Another contribution of the study was to draw attention to the importance of astrocytes in neurological diseases. “The role of glial cells, as in the case of astrocytes, not only in schizophrenia, but in neurological diseases in general, is a recent discovery, as there was a very neurocentric view of the investigation of the role of neurons. It is still a way to broaden our vision and understanding of the disease,” Martins-de-Souza assesses.

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