Su Yixun, Li Hui, Zhang Wenjie, Tao Shi, Wang Qi, Zhang Xuan, Zhou Mi, Huang Xiaomin, Wang Chenmeng, Tang Yong, Chen Hui, Verkhratsky Alexei, Zha Zhengbao, Niu Jianqin, Yi Chenju
Research Centre, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
Department of Histology and Embryology, Third Military Medical University, Chongqing, China.
Nat Commun. 2025 Jul 1;16(1):5621. doi: 10.1038/s41467-025-60746-w.
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 APP/PS1 (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.
阿尔茨海默病（AD）是老年痴呆的主要病因，目前缺乏有效的治疗方法。虽然小胶质细胞在AD病理学中起核心作用，但关键的治疗靶点仍不明确。在此，我们确定小胶质细胞连接蛋白43（Cx43）半通道是AD中小胶质细胞反应性的调节因子，使其成为一个有前景的治疗靶点。AD患者的尸检组织显示，斑块周围小胶质细胞中的Cx43水平升高。在淀粉样变性的APP/PS1小鼠模型中，我们证明小胶质细胞Cx43半通道与小胶质细胞功能障碍相关，进而加剧β淀粉样蛋白病理学。通过基因敲除消除小胶质细胞Cx43半通道可使小胶质细胞转变为神经保护表型，增强小胶质细胞与斑块的相互作用，同时抑制神经毒性，从而减轻AD样病理学的进展。我们开发了TAT-Cx43@LNPs，一种由脂质纳米颗粒系统递送的靶向Cx43半通道的肽，它有效地延缓并挽救了APP/PS1小鼠中与β淀粉样蛋白相关的神经病理学和认知障碍。这项研究为将Cx43半通道靶向治疗推进到临床试验提供了证据。
