Major depressive disorder (MDD) is a prevalent brain disorder affecting more than 2% of the world’s population. Due to the lack of well-specific biomarkers, it is difficult to distinguish MDD from other diseases with similar clinical symptoms (such as Alzheimer’s disease and cerebral thrombosis). In this work, we provided a strategy to address this issue by constructing a combinatorial biomarker of serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NFL). To achieve the convenient and sensitive detection of two proteins, we developed an electrochemical immunosandwich sensor using two metal-ion-doped carbon dots (Pb-CDs and Cu-CDs) as probes for signal output. Each probe contains approximately 300 Pb2+ or 200 Cu2+, providing excellent signal amplification. This method achieved detection limits of 0.3 pg mL–1 for GFAP and 0.2 pg mL–1 for NFL, lower than most of the reported detection limits. Analysis of real serum samples showed that the concentration ratio of GFAP to NFL, which is associated with the relative degree of brain inflammation and neurodegeneration, is suitable for not only distinguishing MDD from healthy individuals but also specifically distinguishing MDD from Alzheimer’s disease and cerebral thrombosis. The good specificity gives the combinatorial GFAP/NFL biomarker broad application prospects in the screening, diagnosis, and treatment of MDD.
Siqiuyue Zhou,Dan Liu,Jia Chen,Chao Xiang,Juan Xiang,Minghui Yang
Serum neurofilament light chain (NFL), a potential general biomarker for neurodegenerative diseases, is not specific enough to differentiate neurodegenerative diseases from other brain diseases such as cerebral thrombosis (CT). According to the importance of glycosylation in neurodegenerative pathogenesis, the NFL glycosylation level (oNFL/tNFL), defined as the ratio of glycosylated NFL (oNFL) to total NFL (tNFL), may be a more effective index. The major challenge in serum oNFL/tNFL detection is the ultra-low abundance of both NFL forms. In this paper, we achieved a convenient one-step electrochemical quantitation of oNFL/tNFL based on an interface-solution dual-path amplification strategy. Two amplified electrochemical signals─the reduction of Cu2+ from adsorbed porous nanoparticles on the sensor interface and the reduction of O2 from horseradish peroxidase-catalyzed H2O2 disproportionation in solution─were adopted to quantify tNFL and oNFL, respectively. The electrochemical sensor displayed good sensitivity, selectivity, and reproducibility. The dynamic range is 1–25 pg mL–1 for tNFL and 0.25–25 pg mL–1 for oNFL, respectively. By analyzing the clinic serum samples, for the first time, our work provided the abundance of oNFL in human serum and revealed that the oNFL/tNFL is effective not only in differentiating three kinds of brain damage patients from healthy people but also in differentiating neurodegeneration from non-neurodegeneration CT patients. As a general biomarker, the oNFL/tNFL is more specific than NFL, which is hoped to be a new and valid indicator for the diagnosis, progression, prediction, and treatment evaluation of neurodegenerative diseases.
The ischemic strokes seriously threaten human health with high incidence and disability rates. Cerebral embolism and impaired brain function are the two major clinical features of this disease. Therefore, rapid restoration of cerebral blood supply and synchronous improvement of impaired neurological function is the key to treating strokes. Herein, based on the microenvironment of cerebral thrombosis and pathological characteristics of damaged neurons, we constructed a shear force and reactive oxygen species (ROS) dual-responsive system (UK@Fuc/CDPC-PTPCS) for sequential targeted delivery of thrombolytic agent urokinase (UK) and neuroprotective drug cytosolic choline (CDPC). Results proved that after intravenous administration, UK@Fuc/CDPC-PTPCS can quickly locate to cerebral thrombosis site via the active recognition capability of fucoidan (Fuc) to P-selectin overexpressed on activated platelets. Subsequently, the sharply increased blood shear force separated the core-shell structure by breaking the host-guest interaction of β-cyclodextrin (β-CD), so the UK loaded in the shell was first released to rapid thrombolysis and then restored cerebral blood supply. Afterward, the stroke homing peptide (SHp) modified CDPC-PTPCS core actively recognized ischemic damaged neuronal cells. Then high intracellular ROS triggered CDPC release at specific sites to exert neuroprotective effects. This study offered a new therapeutic strategy for ischemic stroke.
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