Elevated cleavage of neuregulin-1 by beta-secretase 1 in plasma of schizophrenia patients

Neuregulin 1 (NRG1) is a key candidate susceptibility gene for schizophrenia. It is reported that the function of NRG1 can be regulated by cleavage via the beta-Secretase (BACE1), particularly during early development. While current knowledge suggested that schizophrenia might have different phenotypes, it is unknown whether BACE1-cleaved-NRG1 (BACE1-NRG1) activity is related to clinical phenotypes of schizophrenia. In the current study, we used a newly developed enzymatic assay to detect BACE1-NRG1 activity in the human plasma and investigated the levels of cleavage of NRG1 by BACE1 in the plasma from schizophrenia patients. Our results are the first to demonstrate that the level of plasma BACE1-NRG1 activity was significantly increased in subjects affected with schizophrenia compared with healthy controls. Interestingly, the elevated BACE1-NRG1 activity was correlated with the disease severity and duration of schizophrenia, such as patients suffering from shorter-term course and worse disease status expressed higher BACE1-NRG1 activity levels compared to whom with longer duration and less severity of the disease. Furthermore, this is also the first report that the alternation of BACE1-NRG1 activity was a substrate -specific event in schizophrenia. Together, our findings suggested that the plasma BACE1-NRG1 activity can be a potential biomarker for the early diagnosis of schizophrenia.