Selective connexin43 hemichannel-blocking peptide improves cognition in Alzheimer's mouse model

Researchers found that connexin43 hemichannels open abnormally on reactive astrocytes and microglia near amyloid plaques in Alzheimer's disease brains and APP/PS1 mice, mediating calcium influx and ATP/glutamate release that damage neurons. In collaboration with Aha, they used a TAT-Cx43 peptide, delivered in VPN lipid nanoparticles giving seven-day brain exposure after intraperitoneal injection, to selectively block hemichannels while sparing gap junctions. In APP/PS1 mice, weekly dosing either from 8 months for seven weeks or from 3.5 months for nine weeks improved cognition, reduced oxidative stress and dendritic spine loss, and shifted microglia toward a neuroprotective state.