Yang, TaoKnowles, Juliet K.Lu, QunZhang, HongArancio, OttavioMoore, Laura A.Chang, TimothyWang, QianAndreasson, KatrinRajadas, JayakumarFuller, Gerald G.Xie, YoumeiMassa, Stephen M.Longo, Frank M.2011-04-282011-05-172011-04-282011-05-172008-11-03PLoS ONE; 3:11 p. e3604http://hdl.handle.net/10342/3430The 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 Abinduced 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 signaling pathways, reverse synaptic impairment and inhibit Ab-induced neuronal dystrophy and death. Originally published PLoS ONE, Vol. 3, No. 11, Nov 2008en-USAuthor notified of opt-out rights by Cammie Jennings prior to upload of this article.Alzheimer's diseaseP75 neurotrophin receptorSmall molecule ligandsArticlePMC2575383