proBDNF expression induces apoptosis and inhibits synaptic regeneration by regulating the RhoA-JNK pathway in an in vitro post-stroke depression model

Abstract

Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of post-stroke depression (PSD). However, the precise function and potential mechanism of proBDNF, the precursor form of BDNF, are unknown. In our study, a PSD-like model was established by treating neuronal cells with oxygen-glucose deprivation and corticosterone. We found that the protein proBDNF levels were significantly higher in the cortex and hippocampus in the PSD group than in the control group, suggesting that proBDNF plays a role in the pathophysiology of PSD. Furthermore, we re-established the PSD-like cell model using recombinant p75 neurotrophin receptor (p75NTR) or silencing c-Jun N-terminal kinase (JNK), and found that the PSD-induced upregulation of proBDNF was inhibited by recombinant p75NTR and JNK silencing (siJNK), and increased cellular apoptosis. Moreover, the application of recombinant p75NTR and siJNK in the PSD-like cell model significantly reversed the expression of apoptosis-related and depression-related proteins and decreased cellular apoptosis. Our findings suggest that proBDNF is involved in neural plasticity in PSD in vitro. The RhoA-JNK signaling pathway is activated after proBDNF binds to the p75NTR receptor, followed by the expression of apoptosis-related proteins (PSD95, synaptophysin, and P-cofilin), which contribute to PSD progression. The mechanism might involve the promotion of cellular apoptosis and the inhibition of nerve synapses regeneration by proBDNF.

Aluminium oxide nanoparticles compromise spatial memory performance and proBDNF-mediated neuronal function in the hippocampus of rats

“…More recently, hippocampal glutamate metabolism disorder was found to be induced by treatment with aluminaNPs via activating IFN-γ/ASK1/JNK signaling pathway [ 72 ]. More importantly, the RhoA-JNK pathway can be activated after proBDNF binds to the p75 NTR receptor, which in turn induces oxidative damage and promotes apoptosis, thus affecting synaptic plasticity [ 41 , 78 ]. Therefore, our evidence implies that the activation of proBDNF-RhoA signaling by aluminaNP infusions is an important factor for spatial memory deficits.…”

“…Previous studies have also reported that aluminaNPs can cause oxidative stress and inflammatory events in mouse brains [ 7 , 40 ]. At cellular levels, activation of proBDNF signaling after binding to its receptor p75 NTR plays a major role in neuronal apoptosis and the formation of synaptic plasticity through the activation of the downstream RhoA pathway [ 41 – 43 ]. Together, these findings pointed to significant disruptions to neuronal function within the hippocampus, leading to the prediction that they may underlie at least some of the spatial learning deficits and memory disorders observed following the aluminaNP exposure.…”

Molecular and Functional Characterization of BDNF-Overexpressing Human Retinal Pigment Epithelial Cells Established by Sleeping Beauty Transposon-Mediated Gene Transfer

“…In addition to mature BDNF, pro-BDNF was also detected in the culture supernatants. Pro-BDNF has the opposite effect to mature BDNF: it induces apoptosis and inhibits proliferation [ 87 , 88 , 89 ]. Moreover, several studies have shown that excessive BDNF concentration led to downregulation of the high-affinity receptor TrkB [ 90 , 91 , 92 ].…”

The Role of Brain-Derived Neurotrophic Factor Signaling in Central Nervous System Disease Pathogenesis

“…The expression of BDNF was found to be triggered by brain injury as part of the neuroprotective response following a stroke (Kokaia et al, 1998). Moreover, pro-BDNF plays a role in apoptosis following its binding to the p75NTR receptor, which aggravates post-stroke depression (PSD) (Yang et al, 2021). These results indicate that regulation of the BDNF signaling pathway has the potential to treat brain injury after a stroke.…”