Turning microglia neuroprotective: Towards connexin43-specific therapy of Alzheimer’s disease

Alzheimer’s disease (AD) is the major cause of senile dementia without effective therapeutic strategies. The fundamental role of microglia in AD pathology, particularly in the early stages, is well acknowledged, although cell-specific therapeutic targets were not identified. Here we show that microglial connexin 43 (Cx43) hemichannels controls microglial reactivity in AD, thus being a promising therapeutic target. We discovered a marked increase in Cx43 protein in the periplaque microglia in the post-mortem tissue from AD patients. Subsequently, using the APP _swe /PS1 _dE9 mouse model of AD, we demonstrated that microglial Cx43 operating as hemichannels influences microglial function, which in turn affects β-amyloid pathology. Ablation of microglial Cx43 hemichannels by genetic knockout shifted microglia to neuroprotective phenotype, which promoted the microglia-plaque interaction while suppressing the neurotoxic microglial signature, thereby mitigating the progression of AD. Following this lead, we developed a novel formulation of a small molecule peptide, lipid nanoparticle-delivered molecule TAT-Cx43 _266-283 (TAT-CX43@LNPs), which selectively blocks Cx43 hemichannels. Our preclinical trial demonstrated its efficacy in delaying and rescuing β-amyloid-related neuropathology and cognitive impairment in AD mice. This study provides strong evidence to progress our novel drug into clinical trials and translate it to disease-preventing (when administered in the early disease stages) and disease-modifying agents.