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

• Published in: PloS one 2008-11, Vol.3 (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: Article
• Language: English
• Subjects: AKT protein; Alzheimer's disease; Alzheimers disease; Antigens; Apoptosis; Brain slice preparation; c-Jun protein; Calpain; Cell culture; Chemical engineering; Cyclic AMP response element-binding protein; Cyclin-dependent kinase 5; Deactivation; Death; Degeneration; Dystrophy; Growth factors; Hippocampus; Impairment; Inactivation; Ischemia; Kinases; Ligands; Long-term potentiation; Mortality; Neurodegeneration; Neurodegenerative diseases; Neurological Disorders/Alzheimer Disease; Neurology; Neurons; Neuroscience/Neurobiology of Disease and Regeneration; Peptides; Pharmacology/Drug Development; Phosphatase; Phosphorylation; Proteins; Pyramidal cells; Rodents; Science; Tau protein; Transcription factors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0003604

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 Aβ-induced degeneration and synaptic dysfunction. These ligands inhibited Aβ-induced neuritic dystrophy, death of cultured neurons and Aβ-induced death of pyramidal neurons in hippocampal slice cultures. Moreover, ligands inhibited Aβ-induced activation of molecules involved in AD pathology including calpain/cdk5, GSK3β and c-Jun, and tau phosphorylation, and prevented Aβ-induced inactivation of AKT and CREB. Finally, a p75NTR ligand blocked Aβ-induced hippocampal LTP impairment. These studies support an extensive intersection between p75NTR signaling and Aβ 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 Aβ-induced neuronal dystrophy and death.