Abstract
Accumulating evidence has highlighted the critical involvement of ErbB4 receptor in the onset and progression of Alzheimer's disease (AD). Utilizing a small molecule ErbB4 receptor agonist (E4A) identified through virtual screening, it was observed that activation of ErbB4 receptor significantly ameliorated the cognitive behavioral deficits in APP/PS1 mice. Additionally, E4A treatment enhanced the expression of DOCK3 and SIRT3, leading to improvements in synaptic and mitochondrial dysfunction within the hippocampus of these mice. E4A also attenuated the activation of the TLR4-NF-κB-NLRP3 pathway, thereby reducing neuroinflammation and the formation of β-amyloid (Aβ) plaques. In vitro studies revealed that E4A partially mitigated the impact of hippocampal neuronal damage on microglial inflammation, which was partly compromised by the silencing of DOCK3. Collectively, our data suggest that targeted activation of ErbB4 receptor may treat AD via DOCK3 signaling by inhibiting neuronal damage and subsequent neuroinflammation, thereby offering a viable strategy for this neurodegenerative disease.