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(American Journal of Pathology. 2006;169:119-131.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.050787

Pro-NGF from Alzheimer’s Disease and Normal Human Brain Displays Distinctive Abilities to Induce Processing and Nuclear Translocation of Intracellular Domain of p75NTR and Apoptosis

Petar Podlesniy^*, Anton Kichev^*, Carlos Pedraza^*, Jordi Saurat^*, Mario Encinas, Begoña Perez, Isidre Ferrer and Carme Espinet^*

From the Laboratori de Neuropatología Molecular,^* Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, Lleida, Spain; the Departament Ciències Mèdiques Bàsiques, Laboratori d’Investigació, Hospital Universitari Arnau Vilanova/Universitat de Lleida, Lleida, Spain; and the Institut de Neuropatologia, Servei d’Anatomia Patològica, Hospital de Bellvitge, Universitat de Barcelona, Hospitalet de Llobregat, Barcelona, Spain

The pro form of neurotrophic growth factor (pro-NGF), purified by chromatography from human Alzheimer’s disease (AD)-affected brains (ADhbi-pro-NGF), has been shown to induce apoptotic cell death in neuronal cell cultures through its interaction with the p75 neurotrophin receptor (p75NTR). In the present work, we report that ADhbi-pro-NGF stimulates processing of p75NTR with - and -secretases, yielding a 20-kd intracellular domain (p75^ICD) that translocates to the nucleus. This process was accompanied by delayed apoptosis. In AD, p75^ICD was significantly increased in human entorhinal cortex. Although human frontal cortex has been described as showing a higher pro-NGF increase in AD, the increase in the entorhinal cortex paralleled p75NTR processing in its intracellular domain. In addition, pro-NGF isolated from AD-affected brains differed functionally from pro-NGF isolated from comparably aged control brains, with pro-NGF isolated from control brains being unstable and undergoing degradation to NGF when added to cell culture. As p75^ICD and pro-NGF are both mediators of apoptosis and are both found in increased levels in the cerebral cortex in AD, the present data have implications for understanding neuronal degeneration in AD.

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