| Title | Cell Death and Learning Impairment in Mice Caused by in Vitro Modified Pro-NGF Can Be Related to Its Increased Oxidative Modifications in Alzheimer Disease. | | Author(s) | Kichev A, Ilieva EV, Piñol-Ripoll G, Podlesniy P, Ferrer I, Portero-Otín M, Pamplona R, Espinet C | | Institution | From the Department of Basic Medical Sciences,* University of Lleida-IRBLLEIDA, Lleida, Spain; the Department of Experimental Medicine, University of Lleida-IRBLLEIDA, Lleida, Spain; and the Institute of Neuropathology, Service of Pathologic Anatomy, IDIBELL-University Hospital of Bellvitge, University of Barcelona, CIBERNED, Hospitalet de Llobregat, Barcelona, Spain. | | Source | Am J Pathol 2009 Nov 5. | | Abstract | Pro-nerve growth factor (pro-NGF) is expressed at increased levels in Alzheimer's disease (AD)-affected brains and is able to induce cell death in cultures; however, the reasons for these phenomena remain elusive. Here we show that pro-NGF in human AD-affected hippocampus and entorhinal cortex is modified by advanced glycation and lipoxidation end-products in a stage-dependent manner. These modifications block pro-NGF processing to mature NGF, thus making the proneurotrophin especially effective in inducing apoptosis of PC12 cells in culture through the p75 neurotrophin receptor. The processing of advanced glycation and lipoxidation end-products in vitro modified recombinant human pro-NGF is severely impaired, as evidenced by Western blot and by examining its physiological functionality in cell cultures. We also report that modified recombinant human pro-NGF, as well as pro-NGF isolated from human brain affected by AD, cause impairment of learning tasks when administered intracerebroventricularly in mice, which correlates with AD-associated learning impairment. Taken together, the data we present here offer a novel pathway of ethiopathogenesis in AD caused by advanced glycation and lipoxidation end-products modification of pro-NGF. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19893045 |
|
