Small Molecule, Non-Peptide p75NTR Ligands Inhibit Aß-Induced Neurodegeneration and Synaptic Impairment
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Date
2008-11-03
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Authors
Yang, Tao
Knowles, Juliet K.
Lu, Qun
Zhang, Hong
Arancio, Ottavio
Moore, Laura A.
Chang, Timothy
Wang, Qian
Andreasson, Katrin
Rajadas, Jayakumar
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Publisher
East Carolina University
Abstract
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 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 2008
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Citation
PLoS ONE; 3:11 p. e3604