title: The new β amyloid-derived peptide Aβ1-6A2V-TAT(D) prevents Aβ oligomer formation and protects transgenic C. elegans from Aβ toxicity.
abstract: One attractive pharmacological strategy for Alzheimer's disease (AD) is to design small peptides to interact with amyloid-β (Aβ) protein reducing its aggregation and toxicity. Starting from clinical observations indicating that patients coding a mutated Aβ variant (AβA2V) in the heterozygous state do not develop AD, we developed AβA2V synthetic peptides, as well as a small peptide homologous to residues 1-6. These hindered the amyloidogenesis of Aβ and its neurotoxicity in vitro, suggesting a basis for the design of a new small peptide in D-isomeric form, linked to the arginine-rich TAT sequence [Aβ1-6A2V-TAT(D)], to allow translocation across biological membranes and the blood-brain barrier. Aβ1-6A2V-TAT(D) was resistant to protease degradation, stable in serum and specifically able to interfere with Aβ aggregation in vitro, reducing the appearance of toxic soluble species and protecting transgenic C. elegans from toxicity related to the muscular expression of human Aβ. These observations offer a proof of concept for future pharmacological studies in mouse models of AD, providing a foundation for the design of AβA2V-based peptidomimetic molecules for therapeutic purposes.
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: 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 Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cagnotto
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: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
authors.forename: Marten
authors.initials: M
authors.lastname: Beeg
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: Division of Neurology and Neuropathology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
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: Marco
authors.initials: M
authors.lastname: Gobbi
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: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D009069:Movement Disorders / Q000209:etiology; D009154:Mutation / Q000235:genetics*; D009469:Neuromuscular Junction / Q000503:physiopathology; D020258:Neurotoxicity Syndromes / Q000150:complications / Q000209:etiology / Q000235:genetics; D010243:Paralysis / Q000209:etiology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D011485:Protein Binding; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D020349:Surface Plasmon Resonance
chemical_list: D016229:Amyloid beta-Peptides; D015696:Gene Products, tat; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C505239:amyloid beta-protein (1-6)
keywords: Alzheimer's disease; Amyloid β; Aβ(A2V); C. elegans; Oligomer