Abstract
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.
Highlights
Most studies of the neurobiology of schizophrenia have focused on neurotransmitter systems, their receptors, and downstream effectors
astrocyte-derived exosomes (ADEs) and neuron-derived exosomes (NDEs) of controls and first-episode psychotics (FPs) patients were of similar sizes with diameters ranging from 64 to 120 nm for NDEs and 72–114 nm for ADEs
The neuron marker neuron-specific enolase was at a mean ± S.E.M. of 5,816 ± 142 pg/ml and 5,238 ± 160 pg/ml in control and FP patient NDE extracts, respectively, and 290 ± 31.4 pg/ml and 352 ± 41.8 pg/ml in control and FP patient ADE extracts
Summary
Most studies of the neurobiology of schizophrenia have focused on neurotransmitter systems, their receptors, and downstream effectors. 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[1,2,3,4,5]. In many inflammatory and degenerative neurological diseases, astrocytes increase in number, are transformed into A1 reactive/inflammatorytype astrocytes and contribute to destruction of neurons[7,8,9]. The recently developed capacity to enrich astrocyte-derived exosomes (ADEs) from plasma of living subjects has enabled investigations into the roles of inflammatory astrocytes in Alzheimer’s disease (AD) and traumatic brain injury (TBI)[11,12]
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