Connexin43 hemichannel blockade turns microglia neuroprotective and mitigates cognitive deficits in a mouse model of amyloidosis
Copyright policy )Connexin43 hemichannel blockade turns microglia neuroprotective and mitigates cognitive deficits in a mouse model of amyloidosis
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(swe)/PS1(dE9) (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.
- Chengdu University of Traditional Chinese Medicine China (People's Republic of)
- Third Military Medical University China (People's Republic of)
- University of Salford United Kingdom
- Chongqing University China (People's Republic of)
- University of the Basque Country Spain
Mice, Knockout, Male, Animal, Knockout, Mice, Transgenic, Cognitive Dysfunction/metabolism, Transgenic, Neuroprotection, Presenilin-1/genetics, Article, Microglia/metabolism, Disease Models, Animal, Mice, Disease Models, Animals, Humans, Alzheimer Disease/metabolism, Female, Amyloidosis/metabolism, Plaque, Amyloid/pathology, Connexin 43/metabolism, Amyloid beta-Protein Precursor/genetics, Amyloid beta-Peptides/metabolism, Plaque, Amyloid/pathology
Mice, Knockout, Male, Animal, Knockout, Mice, Transgenic, Cognitive Dysfunction/metabolism, Transgenic, Neuroprotection, Presenilin-1/genetics, Article, Microglia/metabolism, Disease Models, Animal, Mice, Disease Models, Animals, Humans, Alzheimer Disease/metabolism, Female, Amyloidosis/metabolism, Plaque, Amyloid/pathology, Connexin 43/metabolism, Amyloid beta-Protein Precursor/genetics, Amyloid beta-Peptides/metabolism, Plaque, Amyloid/pathology
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