Small Molecule, Non-Peptide p75.sup.NTR Ligands Inhibit A[beta]-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: Public Library of Science 03.11.2008
• Subjects: Advertising executives; Alzheimer's disease; Disease susceptibility; Neurons; Peptides
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0003604

The p75 neurotrophin receptor (p75.sup.NTR) is expressed by neurons particularly vulnerable in Alzheimer's disease (AD). We tested the hypothesis that non-peptide, small molecule p75.sup.NTR ligands found to promote survival signaling might prevent A[beta]-induced degeneration and synaptic dysfunction. These ligands inhibited A[beta]-induced neuritic dystrophy, death of cultured neurons and A[beta]-induced death of pyramidal neurons in hippocampal slice cultures. Moreover, ligands inhibited A[beta]-induced activation of molecules involved in AD pathology including calpain/cdk5, GSK3[beta] and c-Jun, and tau phosphorylation, and prevented A[beta]-induced inactivation of AKT and CREB. Finally, a p75.sup.NTR ligand blocked A[beta]-induced hippocampal LTP impairment. These studies support an extensive intersection between p75.sup.NTR signaling and A[beta] 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 A[beta]-induced neuronal dystrophy and death.