title: Anti-Aβ single-chain variable fragment antibodies exert synergistic neuroprotective activities in Drosophila models of Alzheimer's disease.
abstract: Both active and passive immunotherapy protocols decrease insoluble amyloid-ß42 (Aß42) peptide in animal models, suggesting potential therapeutic applications against the main pathological trigger in Alzheimer's disease (AD). However, recent clinical trials have reported no significant benefits from humanized anti-Aß42 antibodies. Engineered single-chain variable fragment antibodies (scFv) are much smaller and can easily penetrate the brain, but identifying the most effective scFvs in murine AD models is slow and costly. We show here that scFvs against the N- and C-terminus of Aß42 (scFv9 and scFV42.2, respectively) that decrease insoluble Aß42 in CRND mice are neuroprotective in Drosophila models of Aß42 and amyloid precursor protein neurotoxicity. Both scFv9 and scFv42.2 suppress eye toxicity, reduce cell death in brain neurons, protect the structural integrity of dendritic terminals in brain neurons and delay locomotor dysfunction. Additionally, we show for the first time that co-expression of both anti-Aß scFvs display synergistic neuroprotective activities, suggesting that combined therapies targeting distinct Aß42 epitopes can be more effective than targeting a single epitope. Overall, we demonstrate the feasibility of using Drosophila as a first step for characterizing neuroprotective anti-Aß scFvs in vivo and identifying scFv combinations with synergistic neuroprotective activities.
authors.affiliation: Department of Neurology, McKnight Brain Institute, Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease and Genetics Institute, University of Florida, Gainesville, FL 32611, USA pedro.fernandez@neurology.ufl.edu diego.rincon@neurology.ufl.edu.
authors.forename: Pedro
authors.initials: P
authors.lastname: Fernandez-Funez
authors.affiliation: Department of Neurology, McKnight Brain Institute.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, McKnight Brain Institute.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Sanchez-Garcia
authors.affiliation: Department of Neurology, McKnight Brain Institute.
authors.forename: Lorena
authors.initials: L
authors.lastname: de Mena
authors.affiliation: Department of Neurology, McKnight Brain Institute.
authors.forename: Swati
authors.initials: S
authors.lastname: Khare
authors.affiliation: Department of Neurology, McKnight Brain Institute, Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease and.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.affiliation: Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease and.
authors.forename: Yona
authors.initials: Y
authors.lastname: Levites
authors.affiliation: Department of Neurology, McKnight Brain Institute, Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease and Genetics Institute, University of Florida, Gainesville, FL 32611, USA pedro.fernandez@neurology.ufl.edu diego.rincon@neurology.ufl.edu.
authors.forename: Diego E
authors.initials: DE
authors.lastname: Rincon-Limas
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000276:immunology*; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000378:metabolism / Q000473:pathology; D054910:Compound Eye, Arthropod / Q000276:immunology; D004195:Disease Models, Animal; D004330:Drosophila; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004357:Drug Synergism; D005260:Female; D008297:Male; D009043:Motor Activity; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology*; D011994:Recombinant Proteins; D057127:Single-Chain Antibodies / Q000276:immunology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D011994:Recombinant Proteins; D057127:Single-Chain Antibodies; C075222:amyloid beta-protein (1-42)