title: Humanin Specifically Interacts with Amyloid-β Oligomers and Counteracts Their in vivo Toxicity.
abstract: The 24-residue peptide humanin (HN) has been proposed as a peptide-based inhibitor able to interact directly with amyloid-β (Aβ) oligomers and interfere with the formation and/or biological properties of toxic Aβ species. When administered exogenously, HN, or its synthetic S14G-derivative (HNG), exerted multiple cytoprotective effects, counteracting the Aβ-induced toxicity. Whether these peptides interact directly with Aβ, particularly with the soluble oligomeric assemblies, remains largely unknown. We here investigated the ability of HN and HNG to interact directly with highly aggregating Aβ42, and interfere with the formation and toxicity of its oligomers. Experiments were run in cell-free conditions and in vivo in a transgenic C. elegans strain in which the Aβ toxicity was specifically due to oligomeric species. Thioflavin-T assay indicated that both HN and HNG delay the formation and reduce the final amount of Aβ42 fibrils. In vitro surface plasmon resonance studies indicated that they interact with Aβ42 oligomers favoring the formation of amorphous larger assemblies, observed with turbidity and electron microscopy. In vivo studies indicated that both HN and HNG decrease the relative abundance of A11-positive prefibrillar oligomers as well as OC-positive fibrillar oligomers and had similar protective effects. However, while HN possibly decreased the oligomers by promoting their assembly into larger aggregates, the reduction of oligomers caused by HNG can be ascribed to a marked decrease of the total Aβ levels, likely the consequence of the HNG-induced overexpression of the Aβ-degrading enzyme neprilysin. These findings provide information on the mechanisms underlying the anti-oligomeric effects of HN and HNG and illustrate the role of S14G substitution in regulating the in vivo mechanism of action.
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", 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", 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", 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", Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Department of Cardiovascular Research, Unit of Bio-imaging, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Fiordaliso
authors.affiliation: Department of Cardiovascular Research, Unit of Bio-imaging, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Corbelli
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", 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", 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", Milan, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Diomede
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity* / Q000648:ultrastructure; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002942:Circular Dichroism / Q000379:methods; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism; D010243:Paralysis / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology / Q000648:ultrastructure; D020349:Surface Plasmon Resonance
chemical_list: D016229:Amyloid beta-Peptides; D029742:Caenorhabditis elegans Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; C427211:humanin; D015260:Neprilysin
keywords: Alzheimer’s disease; Caenorhabditis elegans; amyloid-β; humanin; inclusion body myositis; oligomers