Connexin43 hemichannel blockade turns microglia neuroprotective and mitigates cognitive deficits in a mouse model of amyloidosis
Yixun Su, Hui Li, Wenjie Zhang, Shi Tao, Qi Wang, Xuan Zhang, Mi Zhou, Xiaomin Huang, Chenmeng Wang, Yong Tang, Hui Chen, Alexei Verkhratsky, Zhengbao Zha, Jianqin Niu, Chenju Yi
Abstract
Alzheimer’s disease (AD), the leading cause of senile dementia, lacks effective therapies. While microglia are central to AD pathology, key therapeutic targets remain unclear. Here we identify microglial connexin43 (Cx43) hemichannels as a regulator of microglial reactivity in AD, positioning them as a promising therapeutic target. Post-mortem AD patient tissue showed elevated Cx43 levels in periplaque microglia. In the APPswe/PS1dE9 (APP/PS1) mouse model of amyloidosis, we demonstrated that microglial Cx43 hemichannels correlated with microglial malfunction, which in turn exacerbated β-amyloid pathology. Ablation of microglial Cx43 hemichannels by genetic knockout shifts microglia to a neuroprotective phenotype, enhancing the microglia-plaque interaction while suppressing neurotoxicity, thereby mitigating the progression of AD-like pathology. We developed TAT-Cx43@LNPs, a Cx43 hemichannel-targeting peptide delivered by a lipid nanoparticle system, which effectively delayed and rescued β-amyloid-related neuropathology and cognitive impairment in APP/PS1 mice. This study provides evidence for advancing Cx43 hemichannel targeting therapy into clinical trials. Microglia play a critical role in Alzheimer’s disease progression. Here, the authors show that knockout of microglial Cx43 or inhibition of Cx43 hemichannels by nanoparticle-delivered peptide mitigates cognitive deficits and neuropathology in APP/PS1 mice by inducing microglia into a neuroprotective state.