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.
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.
Kichev
Anton
A
Department of Basic Medical Sciences, University of Lleida-IRBLLEIDA, Lleida, Spain.
Ilieva
Ekaterina V
EV
Piñol-Ripoll
Gerard
G
Podlesniy
Petar
P
Ferrer
Isidro
I
Portero-Otín
Manuel
M
Pamplona
Reinald
R
Espinet
Carme
C
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
D017127:Glycation End Products, Advanced; D011498:Protein Precursors; D020800:Receptor, Nerve Growth Factor; C489226:pro-nerve growth factor, mouse; D020932:Nerve Growth Factor