Blocking the FAM19A5-LRRC4B complex enhances neurite growth and synapse assembly.

Abstract Disruption in dynamic balance of synapse build-and-removal process is a major cause of neurological diseases, although the mechanisms underlying the brain fine-tunes and balances this process remain poorly understood. Here, we show that FAM19A5 binds to the postsynaptic adhesion molecule LRRC4B via the FAM19A5 binding (FB) domain, suppressing the interaction of LRRC4B with a presynaptic adhesion molecule PTPRF. Decoys with the FB domain bind to FAM19A5 and redirect it away from the FAM19A5-LRRC4B complex, promoting neurite growth and synapse formation of neurons. The anti-FAM19A5 monoclonal antibody NS101 breaks apart the FAM19A5-LRRC4B complex and enables the transfer of FAM19A5 from the brain into the bloodstream, leading to the restoration of synaptic integrity and improve cognitive function in mouse models of Alzheimer’s disease. Together, our findings suggest that blocking the complex with NS101 may offer therapeutic strategy for treating neurodegenerative diseases requiring regeneration of neurites and formation of new synapses.