Alterations of Astrocytes in the Context of Schizophrenic Dementia

Tarasov, Vadim V.; Svistunov, Andrey; Chubarev, Vladimir N.; Sologova, Susanna S.; Mukhortova, Polina; Levushkin, Dmitrii; Somasundaram, Siva G; Kirkland, Cecil E; Бачурин, С. О.; Aliev, Gjumrakch

doi:10.3389/fphar.2019.01612

Cited by 62 publications

(54 citation statements)

References 130 publications

(201 reference statements)

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“…6b). These particular disorders have been associated with dysfunction in L2/3 neurons and astrocytes 128–135 . Together, these data suggest that COVID-19 may partially recapitulate established pathological processes in the brain and provide molecular hypotheses for emerging neurological complaints in COVID-19 survivors.…”

Section: Associations With Chronic Cns Diseasementioning

confidence: 99%

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

Yang

Kern

et al. 2020

Preprint

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Though SARS-CoV-2 primarily targets the respiratory system, it is increasingly appreciated that patients may suffer neurological symptoms of varied severity. However, an unbiased understanding of the molecular processes across brain cell types that could contribute to these symptoms in COVID-19 patients is still missing. Here, we profile 47,678 droplet-based single-nucleus transcriptomes from the frontal cortex and choroid plexus across 10 non-viral, 4 COVID-19, and 1 influenza patient. We complement transcriptomic data with immunohistochemical staining for the presence of SARS-CoV-2. We find that all major cortex parenchymal and choroid plexus cell types are affected transcriptionally with COVID-19. This arises, in part, from SARS-CoV-2 infection of the cortical brain vasculature, meninges, and choroid plexus, stimulating increased inflammatory signaling into the brain. In parallel, peripheral immune cells infiltrate the brain, microglia activate programs mediating the phagocytosis of live neurons, and astrocytes dysregulate genes involved in neurotransmitter homeostasis. Among neurons, layer 2/3 excitatory neurons--evolutionarily expanded in humans--show a specific downregulation of genes encoding major SNARE and synaptic vesicle components, predicting compromised synaptic transmission. These perturbations are not observed in terminal influenza. Many COVID-19 gene expression changes are shared with those in chronic brain disorders and reside in genetic variants associated with cognitive function, schizophrenia, and depression. Our findings and public dataset provide a molecular framework and new opportunities to understand COVID-19 related neurological disease.

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Section: Associations With Chronic Cns Diseasementioning

confidence: 99%

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

Yang

Kern

et al. 2020

Preprint

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“…Most studies of the neurobiology of schizophrenia have focused on neurotransmitter systems, their receptors, and downstream effectors. In the past decade, however, many findings of astroglial cell abnormalities in human brain tissues from schizophrenia patients, involving their numbers, gene expression, neuromediator metabolism and interactions with neurons have suggested a central role in pathogenesis 1 – 5 . Astrocytes are abundant glial cells of the central nervous system that normally serve diverse trophic roles for neurons 6 .…”

Section: Introductionmentioning

confidence: 99%

Decreased mitochondrial electron transport proteins and increased complement mediators in plasma neural-derived exosomes of early psychosis

et al. 2020

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Potentially neurotoxic systems involved in traumatic and degenerative diseases of the brain were assessed in acute psychosis. Astrocyte-derived exosomes (ADEs) and neuron-derived exosomes (NDEs) were immunoprecipitated from plasma of ten untreated first-episode psychotics (FPs) and ten matched normal controls (Cs). Neural mitochondrial electron transport and complement proteins were extracted, quantified by ELISAs and normalized with levels of CD81 exosome marker. Levels of subunits 1 and 6 of NADH-ubiquinone oxidoreductase (complex I) and subunit 10 of cytochrome b-c1 oxidase (complex III), but not of subunit 1 of cytochrome C oxidase (complex IV) or superoxide dismutase 1 (SOD1) were significantly lower in ADEs and NDEs of FPs than Cs. This dysregulated pattern of electron transport proteins is associated with increased generation of reactive oxygen species. ADE glial fibrillary acidic protein levels were significantly higher in FPs than Cs, indicating a higher percentage of inflammatory astrocytes in FPs. ADE levels of C3b opsonin were significantly higher and those of C5b-9 attack complex was marginally higher in FPs than Cs. A significantly lower ADE level of the C3 convertase inhibitor CD55 may explain the higher levels of C3 convertase-generated C3b. ADE levels of the neuroprotective protein leukemia inhibitory factor (LIF) were significantly lower in FPs than Cs, whereas levels of IL-6 were no different. Plasma neural exosome levels of electron transport and complement proteins may be useful in predicting FP and guiding therapy. SOD mimetics, C3 convertase inhibitors and LIF receptor agonists also may have therapeutic benefits in FP.

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“…Plitman and colleagues 23 did not observe a similar relationship between symptom burden and myo-inositol levels, though their measurement was restricted to associative striatum. It is likely that the critical changes in astroglia are regionally distinct, and likely involve ACC preferentially [24][25][26] .…”

Section: Discussionmentioning

confidence: 99%

The trajectory of putative astroglial dysfunction in first episode schizophrenia: A longitudinal 7-Tesla MRS study

Jeon

Mackinley

Théberge

et al. 2021

Preprint

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Astroglial pathology has been long suspected in schizophrenia. Myo-inositol, a metabolic marker particularly abundant in astroglia, is reduced in the anterior cingulate cortex (ACC) of patients with schizophrenia. We investigate the status of astroglial integrity indexed by ACC myo-inositol at the onset and over the first 6 months of treatment of first episode schizophrenia. We employed 7T magnetic resonance spectroscopy (1H-MRS) and quantified myo-inositol spectra at the dorsal ACC in 31 participants; 21 patients with schizophrenia with median lifetime antipsychotic exposure of less than 3 days, followed up after 6 months of treatment, and 10 healthy subjects scanned twice over the same time period. We studied the time by group interaction for myo-inositol after adjusting for gender and age. We report significant reduction in myo-inositol concentration in the ACC in schizophrenia at an early, untreated state of acute illness that improves over time. This trajectory indicates that dynamic astroglial changes are likely to operate in the early stages of schizophrenia. MRS myo-inositol may be a critical marker of amelioration of active psychosis in early stages of schizophrenia.

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Alterations of Astrocytes in the Context of Schizophrenic Dementia

Cited by 62 publications

References 130 publications

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

Decreased mitochondrial electron transport proteins and increased complement mediators in plasma neural-derived exosomes of early psychosis

The trajectory of putative astroglial dysfunction in first episode schizophrenia: A longitudinal 7-Tesla MRS study

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