Study points to relationship between schizophrenia and vascular changes in the brain

A study published in the journal Molecular Psychiatry suggests that schizophrenia may be related to changes in the vascularization of certain regions of the brain.

In their work, researchers from the State University of Campinas (Unicamp), the D’Or Institute of Research and Teaching (Idor) and the Federal University of Rio de Janeiro (UFRJ) observed that neural cells (astrocytes) derived from patients with the disease induce the formation of a greater number of vessels —albeit thinner 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 touch with reality (psychosis), hallucinations (hearing voices, for example), false beliefs (delusions), abnormal thinking and behavior, decreased motivation, and worsening mental function (cognition).

In the study, the researchers focused attention on the role of astrocytes —essential cells 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 pointing out new therapeutic targets, the study advances in understanding the molecular mechanisms of the disease.

“We showed that astrocytes may be involved with a change in the thickness of the vessels in the brain. And this may be related to an important factor in schizophrenia: the decrease in metabolic flow [produção de energia] in certain brain regions. 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 at 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 Post-Doctoral Scholarship granted to Juliana Minardi Nascimento, first author of the article alongside Pablo Trindade, from UFRJ and Idor.

Change in vascularization

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

To do this, the team reprogrammed epithelial cells from patients with schizophrenia and those in the control group to regress to a pluripotent stage characteristic of stem cells (induced pluripotent stem cells, or iPSCs). Then, cell differentiation was induced, transforming the 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 could be involved in the pathogenesis of schizophrenia. In our work, we confirmed this relationship based on studies with induced pluripotent stem cells. as we did”, explains Martins-de-Souza.

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

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

After the proteomic analysis, the researchers performed functional assays. It was observed that the inflammatory response of astrocytes in patients was altered and that the substances they released affected vascularization. Carrying out these tests was part of Trindade’s postdoctoral studies.

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

This trial was conducted by collaborators at the Universidad de Chile (Chile). “Basically, we placed the conditioned media of astrocytes, containing all the substances that these cells secrete, inside the vascular region of fertilized eggs. observe if the substances secreted by the cultivated cells induce or inhibit the vascularization of the egg”, says Trindade.

In addition to modifying vascularization, astrocytes derived from patients with schizophrenia showed a chronic inflammation profile.

“It is known that astrocytes are neural cells that have the role of regulating the immune response in the region. Therefore, it is possible that they are promoting a more immature or less efficient vascularization. We verified that, in comparison with the control group, the derived astrocytes of patients secrete a greater amount of interleukin-8, an inflammation signal and suspected to be the main agent of vascular dysfunction associated with schizophrenia”, explains the researcher to Agência Fapesp.

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

“The symptoms of the disease usually manifest themselves when you are a young adult. But, as we have shown in the work, the glial cells in these patients are different from the beginning, which interferes with neurodevelopment even in the womb. The differentiation and formation of the brain takes place in an altered way. Therefore, it may be that, during the maturation of the brain, facts like what we verified in the study happen: a systematically altered vascularization leading to the malformation of 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 is the case of astrocytes, not only in schizophrenia, but in neurological diseases in general has been a recent finding, as there was a very neurocentric view of investigating the role of neurons further. a way to broaden our view and understanding of the disease”, evaluates Martins-de-Souza.

The article Induced pluripotent stem cell-derived astrocytes from patients with schizophrenia exhibit an inflammatory phenotype that affects vascularization can be read here.