Small molecule, non-peptide p75 ligands inhibit Abeta-induced neurodegeneration and synaptic impairment

• Published in: PloS one Vol. 3; no. 11; p. e3604
• Main Authors: Yang, Tao, Knowles, Juliet K, Lu, Qun, Zhang, Hong, Arancio, Ottavio, Moore, Laura A, Chang, Timothy, Wang, Qian, Andreasson, Katrin, Rajadas, Jayakumar, Fuller, Gerald G, Xie, Youmei, Massa, Stephen M, Longo, Frank M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science (PLoS) 2008
• Subjects: Amyloid beta-Peptides - pharmacology; Animals; Animals, Newborn; Cell Death - drug effects; Cells, Cultured; Hippocampus - drug effects; Ligands; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Degeneration - chemically induced; Nerve Degeneration - prevention & control; Neurons - drug effects; Organ Culture Techniques; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Rats; Rats, Wistar; Receptors, Nerve Growth Factor - agonists; Receptors, Nerve Growth Factor - genetics; Synaptic Transmission - drug effects
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0003604

The p75 neurotrophin receptor (p75(NTR)) is expressed by neurons particularly vulnerable in Alzheimer's disease (AD). We tested the hypothesis that non-peptide, small molecule p75(NTR) ligands found to promote survival signaling might prevent Abeta-induced degeneration and synaptic dysfunction. These ligands inhibited Abeta-induced neuritic dystrophy, death of cultured neurons and Abeta-induced death of pyramidal neurons in hippocampal slice cultures. Moreover, ligands inhibited Abeta-induced activation of molecules involved in AD pathology including calpain/cdk5, GSK3beta and c-Jun, and tau phosphorylation, and prevented Abeta-induced inactivation of AKT and CREB. Finally, a p75(NTR) ligand blocked Abeta-induced hippocampal LTP impairment. These studies support an extensive intersection between p75(NTR) signaling and Abeta 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 Abeta-induced neuronal dystrophy and death.