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

The p75 neurotrophin receptor (p75NTR) is expressed by neurons particularly vulnerable in Alzheimer’s disease (AD). We tested he hypothesis that non-peptide small molecule p75NTR ligands found to promote survival signaling might prevent Abinduced egeneration and synaptic dysfunction. These ligands inhibited Ab-induced neuritic dystrophy death of cultured eurons and Ab-induced death of pyramidal neurons in hippocampal slice cultures. Moreover ligands inhibited Ab-induced ctivation of molecules involved in AD pathology including calpain/cdk5 GSK3b and c-Jun and tau phosphorylation and revented Ab-induced inactivation of AKT and CREB. Finally a p75NTR ligand blocked Ab-induced hippocampal LTP mpairment. These studies support an extensive intersection between p75NTR signaling and Ab pathogenic mechanisms and ntroduce a class of specific small molecule ligands with the unique ability to block multiple fundamental AD-related signaling athways reverse synaptic impairment and inhibit Ab-induced neuronal dystrophy and death. Originally published PLoS ONE Vol. 3 No. 11 Nov 200