title: Amyloid-β reduces the expression of neuronal FAIM-L, thereby shifting the inflammatory response mediated by TNFα from neuronal protection to death.
abstract: The brains of patients with Alzheimer's disease (AD) present elevated levels of tumor necrosis factor-α (TNFα), a cytokine that has a dual function in neuronal cells. On one hand, TNFα can activate neuronal apoptosis, and on the other hand, it can protect these cells against amyloid-β (Aβ) toxicity. Given the dual behavior of this molecule, there is some controversy regarding its contribution to the pathogenesis of AD. Here we examined the relevance of the long form of Fas apoptotic inhibitory molecule (FAIM) protein, FAIM-L, in regulating the dual function of TNFα. We detected that FAIM-L was reduced in the hippocampi of patients with AD. We also observed that the entorhinal and hippocampal cortex of a mouse model of AD (PS1(M146L)xAPP(751sl)) showed a reduction in this protein before the onset of neurodegeneration. Notably, cultured neurons treated with the cortical soluble fractions of these animals showed a decrease in endogenous FAIM-L, an effect that is mimicked by the treatment with Aβ-derived diffusible ligands (ADDLs). The reduction in the expression of FAIM-L is associated with the progression of the neurodegeneration by changing the inflammatory response mediated by TNFα in neurons. In this sense, we also demonstrate that the protection afforded by TNFα against Aβ toxicity ceases when endogenous FAIM-L is reduced by short hairpin RNA (shRNA) or by treatment with ADDLs. All together, these results support the notion that levels of FAIM-L contribute to determine the protective or deleterious effect of TNFα in neuronal cells.
authors: 1] Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Passeig Vall d'Hebron 119-129, Barcelona 08035, Spain [2] Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Campus de Bellaterra (Edifici M), Bellaterra 08193, Spain [3] Centro de Investigación Biomèdica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors: P
authors: P
authors: Carriba
authors: 1] Centro de Investigación Biomèdica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain [2] Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio, Consejo Superior de Investigaciones Cientificas Universidad de Sevilla, c/ Manuel Siurot s/n, Sevilla 41013, Spain [3] Departamento Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla 41012, Spain.
authors: S
authors: S
authors: Jimenez
authors: 1] Centro de Investigación Biomèdica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain [2] Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio, Consejo Superior de Investigaciones Cientificas Universidad de Sevilla, c/ Manuel Siurot s/n, Sevilla 41013, Spain [3] Departamento Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla 41012, Spain.
authors: V
authors: V
authors: Navarro
authors: 1] Centro de Investigación Biomèdica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain [2] Departamento de Biologia Celular, Genetica y Fisiologia. Facultad de Ciencias. IBIMA Universidad de Malaga, Malaga 29071, Spain.
authors: I
authors: I
authors: Moreno-Gonzalez
authors: 1] Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Passeig Vall d'Hebron 119-129, Barcelona 08035, Spain [2] Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Campus de Bellaterra (Edifici M), Bellaterra 08193, Spain [3] Centro de Investigación Biomèdica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors: B
authors: B
authors: Barneda-Zahonero
authors: 1] Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Passeig Vall d'Hebron 119-129, Barcelona 08035, Spain [2] Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Campus de Bellaterra (Edifici M), Bellaterra 08193, Spain [3] Centro de Investigación Biomèdica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors: R S
authors: RS
authors: Moubarak
authors: 1] Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Passeig Vall d'Hebron 119-129, Barcelona 08035, Spain [2] Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Campus de Bellaterra (Edifici M), Bellaterra 08193, Spain [3] Centro de Investigación Biomèdica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors: J
authors: J
authors: Lopez-Soriano
authors: 1] Centro de Investigación Biomèdica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain [2] Departamento de Biologia Celular, Genetica y Fisiologia. Facultad de Ciencias. IBIMA Universidad de Malaga, Malaga 29071, Spain.
authors: A
authors: A
authors: Gutierrez
authors: 1] Centro de Investigación Biomèdica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain [2] Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio, Consejo Superior de Investigaciones Cientificas Universidad de Sevilla, c/ Manuel Siurot s/n, Sevilla 41013, Spain [3] Departamento Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla 41012, Spain.
authors: J
authors: J
authors: Vitorica
authors: 1] Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Passeig Vall d'Hebron 119-129, Barcelona 08035, Spain [2] Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Campus de Bellaterra (Edifici M), Bellaterra 08193, Spain [3] Centro de Investigación Biomèdica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors: J X
authors: JX
authors: Comella
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D048069:Tumor Necrosis Factors / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; C421307:FAIM protein, human; C498892:Faim protein, mouse; D048069:Tumor Necrosis Factors