proBDNF is modified by advanced glycation end products in Alzheimer’s disease and causes neuronal apoptosis by inducing p75 neurotrophin receptor processing
Fleitas Pérez, Catherine
Marfull Oromí, Pau
Egea Navarro, Joaquim
MetadataShow full item record
Alzheimer disease (AD) is a complex pathology related to multiple causes including oxidative stress. Brain-derived neurotrophic factor (BDNF) is a neutrotrophic factor essential for the survival and differentiation of neurons and is considered a key target in the pathophysiology of various neurodegenerative diseases, as for example AD. Contrarily to BDNF, the precursor form of BDNF (proBDNF) induces apoptosis through the specific interaction with p75 and its co-receptor, Sortilin. We used hippocampal tissue and cerebrospinal fluid from AD patients and controls. to study the localization and the levels of proBDNF, p75 and Sortilin as well as the post-traduccional modifications of proBDNF induced by Radical Oxygen Species, by immunofluorescence and Western blot. Differentiation and survival were assessed on differentiated mouse hippocampal neurons derived from postnatal neural stem cells from WT animals or from the transgenic AD animal model APP/PS1ΔE9, based on mutations of familiar AD. In AD patients we observe a significative increase of proBDNF and Sortilin expression and a significative increase of the ratio proBDNF/BDNF in their cerebrospinal fluid compared to controls. In addition, the proBDNF of AD patients is modified by ROS-derived advanced glycation end products, which prevent the processing of the proBDNF to the mature BDNF, leading to an increase of pathogenicity and a decrease of trophic effects. The cerebrospinal fluid from AD patients, but not from controls, induces apoptosis in differentiated hippocampal neurons mainly by the action of AGE-modified proBDNF present in the cerebrospinal fluid of the patients. This effect is triggered by the activation and processing of p75 that stimulate the internalization of the intracellular domain (ICD) within the nucleus causing apoptosis. Induction of apoptosis and p75 ICD internalization by AD patients-derived proBDNF is further enhanced in neuron cultures from the AD model expressing the APP/PS1ΔE9 transgene. Our results indicate the importance of proBDNF neurotoxic signaling in AD pathology essentially by three mechanisms: i) by an increase of proBDNF stability due to ROS-induced post-traductional modifications; ii) by the increase of expression of the p75 co-receptor, Sortilin and iii) by the increase of the basal levels of p75 processing found in AD.
Is part ofMolecular Brain, 2018, vol. 11, núm. 68, p. 1-16
European research projects
The following license files are associated with this item:
Except where otherwise noted, this item's license is described as cc-by (c) Catherine Fleitas et al., 2018
Showing items related by title, author, creator and subject.
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. Podlesniy, Petar; Kichev, Anton Vladimirov; Pedraza, Carlos; Saurat, Jordi; Encinas Martín, Mario; Pérez, Begoña; Ferrer, Isidre; Espinet Mestre, Carme (Elsevier Inc, 2006)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 ...
Egea Navarro, Joaquim; Espinet Mestre, Carme; Soler i Tatché, Rosa Ma.; Dolcet Roca, Xavier; Yuste Mateos, Víctor J. (Víctor José); Encinas Martín, Mario; Iglesias Durán, Montserrat; Rocamora Ibars, Nativitat; Comella i Carnicé, Joan Xavier (Rockefeller University Press, 2001)It has been reported that phosphoinositide 3-kinase (PI 3-kinase) and its downstream target, protein kinase B (PKB), play a central role in the signaling of cell survival triggered by neurotrophins (NTs). In this report, ...
Alzheimer’s disease mutant mice exhibit reduced brain tissue stiffness compared to wild-type mice in both normoxia and following intermittent hypoxia mimicking sleep apnea Menal Castellote, Maria José; Jorba, Ignasi; Torres, Marta; Montserrat i Capdevila, Josep; Gozal, David; Colell, Anna; Piñol Ripoll, Gerard; Navajas, Daniel; Almendros, Isaac; Farré, Ramon (Frontiers Media, 2018)Background: Evidence from patients and animal models suggests that obstructive sleep apnea (OSA) may increase the risk of Alzheimer’s disease (AD) and that AD is associated with reduced brain tissue stiffness. Aim: To ...