title: Role of p75 neurotrophin receptor in the neurotoxicity by beta-amyloid peptides and synergistic effect of inflammatory cytokines.
abstract: The neurodegenerative changes in Alzheimer's disease (AD) are elicited by the accumulation of beta-amyloid peptides (Abeta), which damage neurons either directly by interacting with components of the cell surface to trigger cell death signaling or indirectly by activating astrocytes and microglia to produce inflammatory mediators. It has been recently proposed that the p75 neurotrophin receptor (p75(NTR)) is responsible for neuronal damage by interacting with Abeta. By using neuroblastoma cell clones lacking the expression of all neurotrophin receptors or engineered to express full-length or various truncated forms of p75(NTR), we could show that p75(NTR) is involved in the direct signaling of cell death by Abeta via the function of its death domain. This signaling leads to the activation of caspases-8 and -3, the production of reactive oxygen intermediates and the induction of an oxidative stress. We also found that the direct and indirect (inflammatory) mechanisms of neuronal damage by Abeta could act synergistically. In fact, TNF-alpha and IL-1beta, cytokines produced by Abeta-activated microglia, could potentiate the neurotoxic action of Abeta mediated by p75(NTR) signaling. Together, our results indicate that neurons expressing p75(NTR), mostly if expressing also proinflammatory cytokine receptors, might be preferential targets of the cytotoxic action of Abeta in AD.
authors.affiliation: Department of Biology, University of Bologna, Via Selmi 3, 40126 Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Perini
authors.forename: Vittorina
authors.initials: V
authors.lastname: Della-Bianca
authors.forename: Valeria
authors.initials: V
authors.lastname: Politi
authors.forename: Giuliano
authors.initials: G
authors.lastname: Della Valle
authors.forename: Ilaria
authors.initials: I
authors.lastname: Dal-Pra
authors.forename: Filippo
authors.initials: F
authors.lastname: Rossi
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Armato
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects*; D002999:Clone Cells; D016207:Cytokines / Q000633:toxicity*; D004357:Drug Synergism; D005786:Gene Expression Regulation; D006801:Humans; D007700:Kinetics; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D010446:Peptide Fragments / Q000633:toxicity; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA / Q000235:genetics / Q000502:physiology; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D017384:Sequence Deletion; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D009498:Neurotoxins; D010446:Peptide Fragments; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D011994:Recombinant Proteins; D020917:Receptor, trkA