Abstract
The brain extracellular matrix (ECM) is involved in crucial processes of neural support, neuronal and synaptic plasticity, extrasynaptic transmission, and neurotransmission. ECM is a tridimensional fibrillary meshwork composed of macromolecules that determine its bioactivity and give it unique characteristics. The characterization of the brain ECM is critical to understand its dynamic in SZ. Thus, a comparative study was developed with 71 patients with schizophrenia (SZ) and 70 healthy controls. Plasma of participants was analysed by label-free liquid chromatography–tandem mass spectrometry, and the results were validated using the classical western blot method. Lastly, immunostaining of post-mortem human brain tissue was performed to analyse the distribution of the brain ECM proteins by confocal microscopy. The analysis identified four proteins: fibronectin, lumican, nidogen-1, and secreted protein acidic and rich in cysteine (SPARC) as components of the brain ECM. Statistical significance was found for fibronectin (P = 0.0166), SPARC (P = 0.0003), lumican (P = 0.0012), and nidogen-1 (P < 0.0001) that were decreased in the SZ group. Fluorescence imaging of prefrontal cortex (PFC) sections revealed a lower expression of ECM proteins in SZ. Our study proposes a pathophysiological dysregulation of proteins of the brain ECM, whose abnormal composition leads to a progressive neuronal impairment and consequently to neurodegenerative processes due to lack of neurophysiological support and dysregulation of neuronal homeostasis. Moreover, the brain ECM and its components are potential pharmacological targets to develop new therapeutic approaches to treat SZ.
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Acknowledgement
The authors would like to thank the Galicia Sur Health Research Institute (Instituto de Investigación Sanitaria Galicia Sur) and the University Hospital Complex of Vigo (Complexo Hospitalario Universitario de Vigo) for their support. In addition, the authors are especially thankful for the aid provided by the Psychiatric Nursing and Psychiatry Services of the Álvaro Cunqueiro and Nicolás Peña Hospitals.
Funding
This research was financially backed by the Foundation for Science and Technology (FCT, Fundação para a Ciência e Tecnologia) within the framework of grant SFRH/BD/135623/2018 awarded to Daniela Rodrigues-Amorim. Our research was further supported by the Carlos III Health Institute (ISCIII, Instituto Carlos III) through grant P16/00405, and the Ministry of Health, Equality, and Social Policy (Ministerio de Sanidad, Servicios Sociales e Igualdad) – Government Delegation for the National Plan on Drugs (Delegación del Gobierno para el Plan Nacional sobre Drogas) through grant number 2017I054 awarded to José Manuel Olivares, the Health Knowledge Agency (ACIS, Axencia de Coñecementoen Saúde) grant number PRIS2-17, and the Galician Network for Dementia Research (GAIN, Red Gallega de Investigaciónen Demencias) through grant number IN607C-2017/02 awarded to Carlos Spuch, and Luis Freiría Martínez (GAIN, AxenciaGalega de Innovación) with grant number IN606A-2019/025. Finally, this work was also supported by the Consolidation and structure programme of competitive research units (Consolidación y estructuración de unidades de investigacióncompetitivas) through grant number IN607B 2018/17.
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DRA, TRB, and CS designed the study and acquired data to analysis. DRA, TRB, and CS wrote the article. PFP, MIMA, LFM, CRJ, MCVC, MAA, MLG, EH, AGC, and JMO made substantial contributions to conception and design of the study. All authors read and approved the final version of the manuscript.
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Jose Manuel Olivares declared paid positions, honoraria and advisory boards by Angelini, AstraZeneca, Bristol-Myers, Casen Ricordati, GSK, Janssen, Lilly, Lundbeck, Novartis, Otsuka, Pfizer, Sanofi. The rest of the authors declare no conflict of interest.
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Rodrigues-Amorim, D., Rivera-Baltanás, T., Fernández-Palleiro, P. et al. Changes in the Brain Extracellular Matrix Composition in schizophrenia: A Pathophysiological Dysregulation and a Potential Therapeutic Target. Cell Mol Neurobiol 42, 1921–1932 (2022). https://doi.org/10.1007/s10571-021-01073-8
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DOI: https://doi.org/10.1007/s10571-021-01073-8