Small molecule, non-peptide p75NTR ligands inhibit Aβ-induced neurodegeneration and synaptic impairment. Yang, T, Knowles, J K, Lu, Q, Zhang, H, Arancio, O, Moore, L A, Chang, T, Wang, Q, Andreasson, K, Rajadas, J, Fuller, G., Xie, Y, Massa, S M, & Longo, F M PLoS ONE, 2008. Paper abstract bibtex 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.
@article{yang_small_2008,
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 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.},
Author = {Yang, T and Knowles, J K and Lu, Q and Zhang, H and Arancio, O and Moore, L A and Chang, T and Wang, Q and Andreasson, K and Rajadas, J and Fuller, G.G. and Xie, Y and Massa, S M and Longo, F M},
Journal = {PLoS ONE},
Number = {11},
Title = {Small molecule, non-peptide p75NTR ligands inhibit {Aβ}-induced neurodegeneration and synaptic impairment},
Url = {http://www.scopus.com/inward/record.url?eid=2-s2.0-56149091270&partnerID=40&md5=02b623f6b9db868ddf40a767f45365dd},
Volume = {3},
Year = {2008},
Bdsk-Url-1 = {http://www.scopus.com/inward/record.url?eid=2-s2.0-56149091270&partnerID=40&md5=02b623f6b9db868ddf40a767f45365dd}}
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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. 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