Small Molecule, Non-Peptide p75NTR Ligands Inhibit Ab- Induced Neurodegeneration and Synaptic Impairment

The p75 neurotrophin receptor (p75NTR) is expressed by neurons particularly vulnerable in Alzheimer’s disease (AD). We tested the hypothesis that non-peptide, small molecule p75NTR ligands found to promote survival signaling might prevent Ab-induced degeneration and synaptic dysfunction. These ligands inhibited Ab-induced neuritic dystrophy, death of cultured neurons and Ab-induced death of pyramidal neurons in hippocampal slice cultures. Moreover, ligands inhibited Ab-induced activation of molecules involved in AD pathology including calpain/cdk5, GSK3b and c-Jun, and tau phosphorylation, and prevented Ab-induced inactivation of AKT and CREB. Finally, a p75NTR ligand blocked Ab-induced hippocampal LTP impairment. These studies support an extensive intersection between p75NTR signaling and Ab pathogenic mechanisms, and introduce a class of specific small molecule ligands with the unique ability to block multiple fundamental AD-related signalin