Targeting microglial Cx43 in Alzheimer's disease

ABSTRACT: Alzheimer's disease (AD) remainsis a prevalent major cause of senile dementia without effective therapeutic strategiesy. Although Recent studies highlight the critical role of microglia has been well accepted to play a critical role in AD pathology, particularly in the early stages, this study is the first breakthrough to show, suggesting that modulation of pathological microglial states represents a therapeutic opportunity. Here we provide evidence that microglial connexin 43 (Cx43) hemichannel is the main switch ofs regulate microglial reactivity in the context of AD, as well as a promising hence presenting a potential therapeutic target. We demonstrated a marked increase in Cx43 protein level in the periplaque microglia in the post-mortem tissue from AD patients. In APPswe/PS1dE9 mouse model, we discoveredfound that microglial Cx43 operates as a hemichannel to influence microglial function, which in turn affects in β-amyloid pathology. Ablation of microglial Cx43 hemichannels by genetic knockout screwed microglia to neuroprotective phenotype by promotinges the microglia-plaque interaction while suppressing the neurotoxic microglial signature, and thereby mitigating the progression of AD. Following this lead, wWe developed a novel formulation of small molecule peptide, treatment strategy employing lipid nanoparticle-delivered molecule TAT-Cx43266-283 (TAT-CX43@LNPs), which selectivespecifically targets blocks Cx43 hemichannels, and conducted a. Our preclinical trialstudy that demonstrated its efficacyeffectiveness 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 not only into a therapeutic agent during disease progression but also offer strong preventive benefits when administered early.

ORGANISM(S): Mus musculus

PROVIDER: GSE272781 | GEO | 2025/05/22

REPOSITORIES: GEO