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A link between schizophrenia and vascular changes in the brain

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

Source: FAPESP

A study carried out 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 the State University of Campinas (Unicamp), the D’Or Institute for Research and Teaching (IDOR) and the Federal University of Rio de Janeiro (UFRJ) found a connection between astrocytes (cells of the central nervous system) of patients with schizophrenia and formation of narrow blood vessels.

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

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

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

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

“Our findings highlight the role of astrocytes as a central element in the disease and suggest that, therefore, they can be the target of new therapies”, said Daniel Martins-de-Souza, penultimate author of the article and professor at the Institute of Biology at UNICAMP. FAPESP Agency.

The study was supported by FAPESP through a Thematic Project and a postdoctoral fellowship awarded to Juliana Minardi Nascimento, first author of the article, alongside Pablo Trindade, a researcher linked to UFRJ and IDOR.

abnormal vascularization

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

To that end, they reprogrammed epithelial cells from schizophrenia patients and the control group to become induced pluripotent stem cells (iPSCs). They then induced the iPSCs to differentiate into neural stem cells, which can give rise to neurons and astrocytes.

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

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

“In our analysis of cell proteomes, we observed immunological changes associated with astrocytes. In the case of cells from patients with schizophrenia, we also found differences in the levels of pro-inflammatory cytokines and several other proteins that indicated angiogenic action on cerebral vasculature,” said Nascimento.

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

After the proteomic analysis, the researchers performed functional tests to show that the inflammatory response in the astrocytes of patients with schizophrenia was altered 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) assay. Derived from chicken eggs, CAM has a dense network of blood vessels and is widely used to study angiogenesis.

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

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

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

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

“Astrocytes are known to regulate the 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 controls. IL-8 is pro-inflammatory and is suspected to be the main agent of 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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It shows a brain

“Symptoms of the disease usually manifest themselves in young adulthood, but as our study shows, the glial cells of these patients are different from the beginning, affecting fetal neurodevelopment. Brain differentiation and formation are both altered. It may be the case, therefore, that systematically altered vascularization leads to early brain circuit malformation, and this, in turn, leads to schizophrenia later on,” said Nascimento.

Another point raised in the article is the importance of astrocytes for neurological disorders.

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

About this schizophrenia and neuroscience research news

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

Original search: Closed access.
“Astrocytes derived from induced pluripotent stem cells from patients with schizophrenia exhibit an inflammatory phenotype that affects vascularization” by Daniel Martins-de-Souza et al. Molecular Psychiatry


Summary

Astrocytes derived from induced pluripotent stem cells from patients with schizophrenia exhibit an inflammatory phenotype that affects vascularity

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

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

Proteomic analysis revealed alterations in proteins related to immune function and vascularization. Reduced expression of the nuclear factor kappa B (NF-κB) p65 subunit was observed in these astrocytes, without incremental cytokine secretion after stimulation of tumor necrosis factor alpha (TNF-α).

Among inflammatory cytokines, interleukin (IL)-8 secretion was particularly elevated in conditioned media derived from astrocytes from SCZ patients (ASCZCM). In a chicken chorioallantoic membrane (CAM) assay, ASCZCM reduced the diameter of newly grown vessels. This effect can be mimicked with exogenous addition of IL-8.

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

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