title: Aβ1-42 monomers or oligomers have different effects on autophagy and apoptosis.
abstract: The role of autophagy and its relationship with apoptosis in Alzheimer disease (AD) pathogenesis is poorly understood. Disruption of autophagy leads to buildup of incompletely digested substrates, amyloid-β (Aβ) peptide accumulation in vacuoles and cell death. Aβ, in turn, has been found to affect autophagy. Thus, Aβ might be part of a loop in which it is both the substrate of altered autophagy and its cause. Given the relevance of different soluble forms of Aβ1-42 in AD, we have investigated whether monomers and oligomers of the peptide have a differential role in causing altered autophagy and cell death. Using differentiated SK-N-BE neuroblastoma cells, we found that monomers hamper the formation of the autophagic BCL2-BECN1/Beclin 1 complex and activate the MAPK8/JNK1-MAPK9/JNK2 pathway phosphorylating BCL2. Monomers also inhibit apoptosis and allow autophagy with intracellular accumulation of autophagosomes and elevation of levels of BECN1 and LC3-II, resulting in an inhibition of substrate degradation due to an inhibitory action on lysosomal activity. Oligomers, in turn, favor the formation of the BCL2-BECN1 complex favoring apoptosis. In addition, they cause a less profound increase in BECN1 and LC3-II levels than monomers without affecting the autophagic flux. Thus, data presented in this work show a link for autophagy and apoptosis with monomers and oligomers, respectively. These studies are likely to help the design of novel disease modifying therapies.
authors.affiliation: Department of Neuroscience; University of Torino; Torino, Italy; Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO); University of Torino; Torino, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Guglielmotto
authors.affiliation: Department of Clinical and Biological Sciences; University of Torino; Torino, Italy; Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO); University of Torino; Torino, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Monteleone
authors.affiliation: Department of Neuroscience; University of Torino; Torino, Italy; Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO); University of Torino; Torino, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Piras
authors.affiliation: Department of Neuroscience; University of Torino; Torino, Italy; Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO); University of Torino; Torino, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Valsecchi
authors.affiliation: Department of Neuroscience; University of Torino; Torino, Italy; Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO); University of Torino; Torino, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Tropiano
authors.affiliation: Department of Clinical and Biological Sciences; University of Torino; Torino, Italy; Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO); University of Torino; Torino, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Ariano
authors.affiliation: Scienza della Formazione; University of Catania; Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Fornaro
authors.affiliation: Department of Neuroscience; University of Torino; Torino, Italy; Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO); University of Torino; Torino, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vercelli
authors.affiliation: Department of Fundamental Neurosciences; Faculty of Biology and Medicine; University of Lausanne; Lausanne, Switzerland; Clinic of Neonatology; Department of Pediatrics and Pediatric Surgery; Lausanne University Hospital and University of Lausanne; Lausanne, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Puyal
authors.affiliation: Department of Pathology and Cell Biology; Taub Institute for Research on Alzheimer's Disease and the Aging Brain; Columbia University; New York, NY USA.
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.affiliation: Department of Internal Medicine; Unit of Geriatric Medicine; University of Genoa; Genoa, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Tabaton
authors.affiliation: Department of Neuroscience; University of Torino; Torino, Italy; Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO); University of Torino; Torino, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Tamagno
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000473:pathology; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D055503:Protein Multimerization; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer disease; BCL2; BECN1; apoptosis; autophagy; soluble β-amyloid 42