Blocking the FAM19A5-LRRC4B complex enhances neurite growth and synapse assembly.(science ver.)

Abstract

Disruption in the dynamic balance of the synapse build-and-removal process is a major cause of neurological diseases, although the mechanisms underlying how the brain fine-tunes and balances this process remain poorly understood. Here, we demonstrate that FAM19A5 binds to the postsynaptic adhesion molecule LRRC4B and suppresses interaction between LRRC4B and presynaptic PTPRF, suggesting a role of FAM19A5 in synapse assembly. Decoys with the FAM19A5 binding (FB) domain redirect FAM19A5, promoting synapse formation. The anti-FAM19A5 antibody NS101 disrupts the FAM19A5-LRRC4B complex, transferring FAM19A5 from the brain to the bloodstream, restoring synaptic integrity and improving cognitive function in Alzheimer's mouse models. Our findings suggest NS101 could be a therapeutic strategy for neurodegenerative diseases requiring regeneration of neurites and formation of new synapses.