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.
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.
authors.affiliation: Department of Basic Medical Sciences, University of Lleida-IRBLLEIDA, Lleida, Spain.
authors.forename: Anton
authors.initials: A
authors.lastname: Kichev
authors.forename: Ekaterina V
authors.initials: EV
authors.lastname: Ilieva
authors.forename: Gerard
authors.initials: G
authors.lastname: Piñol-Ripoll
authors.forename: Petar
authors.initials: P
authors.lastname: Podlesniy
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
authors.forename: Manuel
authors.initials: M
authors.lastname: Portero-Otín
authors.forename: Reinald
authors.initials: R
authors.lastname: Pamplona
authors.forename: Carme
authors.initials: C
authors.lastname: Espinet
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D007859:Learning Disabilities / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D020932:Nerve Growth Factor / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D016716:PC12 Cells; D011498:Protein Precursors / Q000378:metabolism*; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism
chemical_list: D017127:Glycation End Products, Advanced; D011498:Protein Precursors; D020800:Receptor, Nerve Growth Factor; C489226:pro-nerve growth factor, mouse; D020932:Nerve Growth Factor