ErbB4 mediates amyloid β-induced neurotoxicity through JNK/tau pathway activation: Implications for Alzheimer's disease

Accumulation of amyloid beta (A beta) in the brain is a hallmark of Alzheimer's disease (AD). We previously showed that ErbB4 in parvalbumin (PV)-positive interneurons was associated with A beta-induced cognitive deficits; however, the underlying mechanism remains undetermined. Here we found that specific deletion of ErbB4 in PV neurons significantly attenuated oligomeric A beta-induced neuronal toxicity and inhibited A beta-induced decreases of PSD95 and synaptophysin. Moreover, specific ablation of ErbB4 in PV neurons altered activity-related protein c-Fos and decreased hippocampal PV neurons, especially in the dentate gyrus (DG) of hAPP-J20 mice. Furthermore, c-Jun N-terminal kinase (JNK), a protein downstream of ErbB4, was activated by A beta but not ErbB4's ligand neuregulin 1 (NRG1) beta 1, suggesting different downstream pathways for A beta and NRG1 beta 1. JNK phosphorylation was inhibited by the ErbB4 inhibitor AG1478 and by pretreatment with NRG1 beta 1. More importantly, siRNA knockdown of ErbB4 decreased JNK phosphorylation and expression, tau phosphorylation at Ser396 and Thr 205, and Bax expression. Therefore, ErbB4 might mediate AO-induced neuropathology through the JNK/tau pathway and represent a potential therapeutic target in patients with AD.

Automated summary

The specific deletion of ErbB4 in parvalbumin neurons attenuated A beta-induced neuronal toxicity, decreased synaptic proteins levels and altered activity-related proteins. JNK pathway may mediate A beta-induced neuropathology through ErbB4, providing a potential therapeutic target in Alzheimer's disease.