Small molecule, non-peptide p75 ligands inhibit Abeta-induced neurodegeneration and synaptic impairment.
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.
Yang
Tao
T
Department of Neurology and Neurological Science, Stanford University, Stanford, California, USA.
Knowles
Juliet K
JK
Lu
Qun
Q
Zhang
Hong
H
Arancio
Ottavio
O
Moore
Laura A
LA
Chang
Timothy
T
Wang
Qian
Q
Andreasson
Katrin
K
Rajadas
Jayakumar
J
Fuller
Gerald G
GG
Xie
Youmei
Y
Massa
Stephen M
SM
Longo
Frank M
FM
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D006624:Hippocampus / Q000187:drug effects; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017475:Receptors, Nerve Growth Factor / Q000819:agonists* / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects*
D016229:Amyloid beta-Peptides; D008024:Ligands; D010446:Peptide Fragments; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse