A link between schizophrenia and vascular changes in the brain

Overview: A new study reveals a link between astrocytes from patients with schizophrenia and the formation of narrower blood vessels in the brain. Findings suggest that the astrocytes of people with schizophrenia promote less vascularization.

Source: FAPESP

A study conducted in Brazil and reported in an article published in Molecular Psychiatry suggests that schizophrenia may be associated with changes in the vascularization of certain brain regions.

Researchers from Campinas State University (UNICAMP), the D’Or Research and Education Institute (IDOR) and the Federal University of Rio de Janeiro (UFRJ) found a link between astrocytes (cells of the central nervous system) from patients with schizophrenia and the formation of narrow blood vessels.

Schizophrenia is a serious multifactorial mental disorder that affects approximately 1% of the world’s population. Common symptoms include loss of contact with reality (psychosis), hallucinations (for example, hearing voices), delusions or delirium, disorganized motor behavior, loss of motivation, and cognitive impairment.

In the study, the researchers focused on the role of astrocytes in the development of the disease. These glial cells are housekeepers of the central nervous system and important for its defense. They are the central elements of the neurovascular units that integrate neural circuits with local blood flow and provide neurons with metabolic support.

The study points to new therapeutic targets and advances scientists’ understanding of the molecular mechanisms behind schizophrenia.

“We show that astrocytes may be involved in a change in the thickness of blood vessels in the brain, which in turn may be associated with a reduction in metabolic flux in certain brain regions, a key factor in schizophrenia.

“Our findings highlight the role of astrocytes as a central element in disease and therefore suggest that they may be targets for new therapies,” said Daniel Martins-de-Souza, penultimate author of the paper and a professor at UNICAMP’s Institute. or Biology. Agência FAPESP.

The study was supported by FAPESP through a thematic project and a postdoctoral fellowship awarded to Juliana Minardi Nascimento, first author of the article, together with Pablo Trindade, a researcher associated with UFRJ and IDOR.

Abnormal vascularization

The researchers compared astrocytes from skin cells from schizophrenic patients with others from people without the disease. This portion of the research was conducted in the lab of Stevens Rehen, a researcher at IDOR and a professor at UFRJ’s Institute of Biology.

To this end, they reprogrammed epithelial cells from patients with schizophrenia and the control group into induced pluripotent stem cells (iPSCs). They then caused differentiation of the iPSCs into neural stem cells, which can give rise to both neurons and astrocytes.

“Previous research has suggested that both molecular and functional abnormalities of astrocytes may be involved in the pathogenesis of schizophrenia. In our study, we proved this involvement using iPSCs. Without this technique it would be impossible to study astrocytes as we did,’ said Martins-de-Souza.

The researchers performed two sets of tests using astrocytes from patients and healthy controls. The first was a proteomic analysis in which all proteins in each sample were identified to detect differences between the two sets of astrocytes. This part was performed in UNICAMP’s Laboratory of Neuroproteomics.

“In our analysis of the cells’ proteomes, we observed immune changes associated with astrocytes. In the case of the cells of patients with schizophrenia, we also found differences in the levels of proinflammatory cytokines and several other proteins that indicated angiogenic action in brain vascularization,” Nascimento said.

Angiogenesis is the physiological process by which new blood vessels form from pre-existing blood vessels. It is a normal part of growth and healing, but may play a role in disease.

After the proteomic analysis, the researchers performed functional studies to show that the inflammatory response in the astrocytes of patients with schizophrenia had changed and that the cells secreted substances that affected vascularization. These tests were part of Pablo Trindade’s postdoctoral research.

The model of the vascular system they used is known as the Chicken Chorioallantoic Membrane (CAM) test. Derived from chicken eggs, the CAM has a dense network of blood vessels and is widely used to study angiogenesis.

The test was conducted by researchers at the University of Chile in Santiago, Chile. “Simply put, we placed conditioned astrocyte media containing all the substances secreted by these cells into the vascular region of fertilized eggs.

As the vascular cells multiplied, it was possible to see how the vessel formation proceeded as egg vascularization could be induced or inhibited by the secreted substances,” Trindade said.

In addition to their effects on vascularization, astrocytes from patients with schizophrenia showed chronic inflammation.

This shows a brain
Schizophrenia is a serious multifactorial mental disorder that affects approximately 1% of the world’s population. The image is in the public domain

“Astrocytes are known to regulate immune response in the central nervous system, so it is possible that they promote more immature or less efficient vascularization. Our patient-derived astrocytes secreted more interleukin-8 (IL-8) than the controls. IL-8 is pro-inflammatory and is suspected to be the major cause of the vascular dysfunction associated with schizophrenia,” he said.

According to the authors, the findings reinforce the role of neurodevelopment in schizophrenia and clearly show that astrocytes are important as mediators.

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This shows a brain

“The symptoms of the disease usually manifest in young adulthood, but as our study shows, the glial cells of these patients are different from the start, which affects the neurological development of the fetus. Differentiation and brain formation are both changed. It may therefore be the case that systematically altered vascularization leads to early brain circuit malformation, and this in turn later leads to schizophrenia,” Nascimento said.

Another point made in the article is how important astrocytes are to neurological disorders.

“The role of glial cells, including astrocytes, not only in schizophrenia, but also in neurological disorders in general, has been discovered relatively recently. The predominant view used to be that researchers should focus on neurons. Our vision and understanding of the disease is expanding,” said Martins-de-Souza.

About this news about schizophrenia and neuroscience research

Writer: Heloisa Reinert
Source: FAPESP
Contact: Heloisa Reinert – FAPESP
Image: The image is in the public domain

Original research: Closed access.
“Induced pluripotent stem cell-derived astrocytes from patients with schizophrenia show an inflammatory phenotype affecting vascularization” by Daniel Martins-de-Souza et al. Molecular Psychiatry


Induced pluripotent stem cell-derived astrocytes from patients with schizophrenia show an inflammatory phenotype affecting vascularization

Molecular and functional abnormalities of astrocytes have been implicated in the etiology and pathogenesis of schizophrenia (SCD).

In this study, we investigated the proteome, inflammatory responses and secretome effects on vascularization of human induced pluripotent stem cell (hiPSC)-derived astrocytes from patients with SCD.

Proteomic analysis revealed changes in proteins related to immune function and vascularization. Decreased expression of the nuclear factor kappa B (NF-κB) p65 subunit was observed in these astrocytes, without increasing cytokine secretion following tumor necrosis factor-alpha (TNF-a) stimulation.

Among the inflammatory cytokines, interleukin (IL)-8 secretion was particularly increased in SCZ patient-derived astrocyte-conditioned medium (ASBSCM). In a chicken chorioallantoic membrane (CAM) assay, ASBSCM reduced the diameter of newly grown vessels. This effect could be mimicked with exogenous addition of IL-8.

Taken together, our results suggest that SCD astrocytes are immunologically dysfunctional and, consequently, may affect vascularization through secreted factors.

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