title: Expression of A2V-mutated Aβ in Caenorhabditis elegans results in oligomer formation and toxicity.
abstract: Although Alzheimer's disease (AD) is usually sporadic, in a small proportion of cases it is familial and can be linked to mutations in β-amyloid precursor protein (APP). Unlike the other genetic defects, the mutation [alanine-673→valine-673] (A673V) causes the disease only in the homozygous condition with enhanced amyloid β (Aβ) production and aggregation; heterozygous carriers remain unaffected. It is not clear how misfolding and aggregation of Aβ is affected in vivo by this mutation and whether this correlates with its toxic effects. No animal models over-expressing the A673V-APP gene or alanine-2-valine (A2V) mutated human Aβ protein are currently available. Using the invertebrate Caenorhabditis elegans, we generated the first transgenic animal model to express the human Aβ1-40 wild-type (WT) in neurons or possess the A2V mutation (Aβ1-40A2V). Insertion of an Aβ-mutated gene into this nematode reproduced the homozygous state of the human pathology. Functional and biochemical characteristics found in the A2V strain were compared to those of transgenic C. elegans expressing Aβ1-40WT. The expression of both WT and A2V Aβ1-40 specifically reduced the nematode's lifespan, causing behavioral defects and neurotransmission impairment which were worse in A2V worms. Mutant animals were more resistant than WT to paralysis induced by the cholinergic agonist levamisole, indicating that the locomotor defect was specifically linked to postsynaptic dysfunctions. The toxicity caused by the mutated protein was associated with a high propensity to form oligomeric assemblies which accumulate in the neurons, suggesting this to be the central event involved in the postsynaptic damage and early onset of the disease in homozygous human A673V carriers.
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy. Electronic address: luisa.diomede@marionegri.it.
authors.forename: Luisa
authors.initials: L
authors.lastname: Diomede
authors.affiliation: Division of Neurology and Neuropathology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Fede
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Romeo
authors.affiliation: Department of Environmental Health Sciences, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Bagnati
authors.affiliation: Proteomics Unit, IRCCS "Centro S. Giovanni di Dio-Fatebenefratelli", Via Pilastroni 4, 25125 Brescia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ghidoni
authors.affiliation: Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Fiordaliso
authors.affiliation: Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Salio
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Division of Neurology and Neuropathology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Catania
authors.affiliation: Proteomics Unit, IRCCS "Centro S. Giovanni di Dio-Fatebenefratelli", Via Pilastroni 4, 25125 Brescia, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Paterlini
authors.affiliation: Proteomics Unit, IRCCS "Centro S. Giovanni di Dio-Fatebenefratelli", Via Pilastroni 4, 25125 Brescia, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Benussi
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bastone
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Stravalaci
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.affiliation: Division of Neurology and Neuropathology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)
keywords: A673V mutation; Alzheimer's disease; Amyloid β peptides; Caenorhabditis elegans; Toxic oligomers