Cerebrospinal fluid concentration of complement component 4A is increased in first-episode schizophrenia

Abstract

Excessive synapse loss is a core feature of schizophrenia and is linked to the complement component 4A gene (C4A). In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in first-episode psychosis patients who develop schizophrenia and correlates with CSF measurements of synapse density. Using patient-derived cellular modeling, we find that disease-associated cytokines increase neuronal C4A expression and that IL-1beta associates with C4A in patient-derived CSF.

Neuroimmune cortical organoids overexpressing C4A exhibit multiple schizophrenia endophenotypes

“…Proinflammatory cytokine expression can be monitored as a hallmark disease phenotype as continually activated microglia become detrimental to neuronal health 31 . Chronically activated microglia and cytokine expression have been associated with SCZ, multiple sclerosis, Alzheimer’s and Huntington’s disease and linked to excessive synapse pruning, neuronal death, and astrogliosis 6,32 . Overexpression of C4A in human NICOs does not hinder microglia integration (Fig.…”

“…The largest genetic risk factors for SCZ are associated with the immune-linked major histocompatibility complex (MHC) and complement component 4 (C4) genes consisting of C4A and C4B 4,5 . Increased copy number variants of C4A correlate with increased SCZ risk 5 , with elevated levels of C4A found in post-mortem brain samples 5 and cerebrospinal fluid (CSF) of patients with SCZ 6 . Increased complement C3 deposition on synaptic structures, initiated by C4 in the complement cascade, play a pivotal role in microglia-mediated elimination of synapses 7,8 .…”