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(American Journal of Pathology. 2005;166:533-543.)
© 2005 American Society for Investigative Pathology

Pro-NGF Isolated from the Human Brain Affected by Alzheimer’s Disease Induces Neuronal Apoptosis Mediated by p75NTR

Carlos E. Pedraza*, Petar Podlesniy*, Noemí Vidal{dagger}, Juan Carlos Arévalo{ddagger}, Ramee Lee§, Barbara Hempstead§, Isidre Ferrer{dagger}, Montse Iglesias* and Carme Espinet*

From the Laboratori de Neuropatología Molecular,* Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, Lleida, Spain; the Institut de Neuropatologia,{dagger} Servei d’Anatomia Patològica, Hospital de Bellvitge, Universitat de Barcelona, Hospitalet de Llobregat, Barcelona, Spain; the Molecular Neurobiology Program,{ddagger} Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York; and the Division of Hematology,§ Department of Medicine, Weill Medical College of Cornell University, New York, New York

The pro-form of nerve growth factor (pro-NGF) has been shown to be a high affinity ligand for p75NTR and to induce apoptosis through this receptor. It has been reported that pro-NGF, rather than mature NGF, is the predominant form of this neurotrophin in human brain. In the present work we studied the potential involvement of pro-NGF purified from human brains affected by Alzheimer’s disease (AD), where it is especially abundant, in the neuronal apoptosis observed in this disease. Western blot analysis of human brain tissue showed the existence of several pro-NGF forms. Some of these pro-NGF forms were significantly increased in AD brain cortex in a disease stage-dependent manner. Pro-NGF, purified by chromatography from human AD brains, induced apoptotic cell death in sympathetic neurons and in a p75NTR stably transfected cell line. Blocking p75NTR in cell culture abolished neuronal apoptosis caused by pro-NGF. p75NTR-transfected cells underwent apoptosis in the presence of pro-NGF while control wild-type cells did not. Taken together, these results indicate that pro-NGF purified from AD human brains can induce apoptosis in neuronal cell cultures through its interaction with the p75NTR receptor.





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