Neuregulin-1 Exerts Protective Effects Against Neurotoxicities Induced by C-Terminal Fragments of APP via ErbB4 Receptor

Abstract

Neuregulin-1 (NRG1) plays important roles in the development and plasticity of the brain, and it is also reported to have potent neuroprotective properties. We previously reported that NRG1 has neuroprotective actions against Swedish amyloid precursor protein-induced neurotoxicity. In addition to the amyloid beta peptide, other metabolites of amyloid precursor protein (APP) such as the C-terminal fragments of APP (APP-CTs) have been reported to possess cytotoxic effects in neuronal cells. In this study, we investigated whether NRG1 exerts neuroprotective effects against APP-CTs and attempted to determine its neuroprotective mechanisms. NRG1 attenuated the neurotoxicities induced by the expression of APP-CTs in neuronal cells. NRG1 also reduced the accumulation of reactive oxygen species and attenuated mitochondrial membrane potential loss induced by APP-CTs. In addition, NRG1 upregulated the expression of the anti-apoptotic protein Bcl-2. This effect was blocked by the inhibition of ErbB4, a key NRG1 receptor. Taken together, these results demonstrate the neuroprotective potential of NRG1 in Alzheimer's disease.

Blocking the phosphatidylinositol 3-kinase pathway inhibits neuregulin-1-mediated rescue of neurotoxicity induced by Aβ1–42

“…[36,37] Our earlier study has demonstrated that NRG1 protects the Ab, Swe-APP or C-terminal fragment of APP, which induces cell death and oxidative stress via ErbB4 receptor activation. [27,28] Several studies have demonstrated that ROS are involved in the apoptotic mechanisms that are induced by Ab-mediated neurotoxicity and may, therefore, contribute to the increased apoptosis that is observed in some models of AD. [38,39] Dead neurons in AD may exhibit typical features of apoptosis, such as chromatin condensation and DNA fragmentation.…”

“…[38,39] Dead neurons in AD may exhibit typical features of apoptosis, such as chromatin condensation and DNA fragmentation. [40,41] Cells that are exposed to micromolar concentrations of Ab [25][26][27][28][29][30][31][32][33][34][35] exhibited an increased production of ROS in PC12 cells. [42] NRG1 reduces ROS accumulation that is induced by Swe-APP or APP-CTs in SH-SY5Y cells.…”

“…[26] We also found that NRG1 has neuroprotective effects induced by Swedish amyloid precursor protein, Ab or C-terminal fragments of APP via the ErbB4 receptor. [27,28] These findings suggest that NRG1 signalling may be involved in the pathophysiology of AD by modulating synaptic plasticity and neuronal survival.…”

Down-regulation of PRKCB1 expression in Han Chinese patients with subsyndromal symptomatic depression

“…In fact, there are some lines of evidence suggesting the ERBB signaling pathway plays an important role in cognitive function and brain molecular structure. In humans, impaired ERBB signaling pathway has been associated with the development of neurodegenerative diseases, such as Alzheimer's disease (Ryu et al, 2012) and schizophrenia (Fazzari et al, 2010;Pitcher et al, 2011). In rodents, dysfunction of the ERBB signaling pathway might contribute to cognitive deficiencies (Makinodan et al, 2012) after early social isolation.…”

Neuregulin 1 Controls Glutamate Uptake by Up-regulating Excitatory Amino Acid Carrier 1 (EAAC1)

“…Knock-down of ErbB4 by siRNA Inhibits NRG1 from Up-regulating EAAC1-To investigate the involvement of endogenous ErbB4, we employed siRNA to knock down ErbB4 (24,25). Four different siRNA reduced the ErbB4 protein expression to different degrees (Fig.…”