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AAV-mediated neuronal expression of a scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models

Maria Clara Selles, Juliana T.S. Fortuna, Magali C. Cercato, Luis Eduardo Santos, Luciana Domett, Andre L.B. Bitencourt, Mariane Favero Carraro, Amanda S. Souza, Helena Janickova, Jorge M. de Souza, Soniza Alves-Leon, View ORCID ProfileVania F. Prado, Marco A. M. Prado, Alberto L. Epstein, Anna Salvetti, Ottavio Arancio, William L. Klein, Adriano Sebollela, Fernanda G. De Felice, Diana A. Jerusalinsky, Sergio T. Ferreira
doi: https://doi.org/10.1101/2022.06.10.495369
Maria Clara Selles
1Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
2Skirball Institute for Biomolecular Medicine, New York University Grossman School of Medicine, New York, NY, USA
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Juliana T.S. Fortuna
3Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Magali C. Cercato
4Laboratorio de Neuroplasticidad y Neurotoxinas, Instituto de Biología Celular y Neurociencia “Profesor Eduardo De Robertis”, Universidad de Buenos Aires/CONICET, Buenos Aires, Argentina
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Luis Eduardo Santos
1Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Luciana Domett
3Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Andre L.B. Bitencourt
5Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
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Mariane Favero Carraro
5Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
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Amanda S. Souza
1Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Helena Janickova
6Department of Physiology & Pharmacology and Department of Anatomy & Cell Biology, Robarts Research Institute, The University of Western Ontario, London, Canada
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Jorge M. de Souza
7Division of Neurosurgery and Division of Neurology/Epilepsy Program, Clementino Fraga Filho University Hospital, Rio de Janeiro, Brazil
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Soniza Alves-Leon
7Division of Neurosurgery and Division of Neurology/Epilepsy Program, Clementino Fraga Filho University Hospital, Rio de Janeiro, Brazil
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Vania F. Prado
6Department of Physiology & Pharmacology and Department of Anatomy & Cell Biology, Robarts Research Institute, The University of Western Ontario, London, Canada
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  • ORCID record for Vania F. Prado
Marco A. M. Prado
6Department of Physiology & Pharmacology and Department of Anatomy & Cell Biology, Robarts Research Institute, The University of Western Ontario, London, Canada
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Alberto L. Epstein
8UMR INSERM U1179-UVSQ, Université de Versailles Saint Quentin en Yvelines, 78180 Montigny-le-Bretonneux, France
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Anna Salvetti
9INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
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Ottavio Arancio
10Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, USA
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William L. Klein
11Department of Neurobiology, Northwestern University, Evanston, USA
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Adriano Sebollela
5Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
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Fernanda G. De Felice
1Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
12Centre for Neuroscience Studies & Department of Psychiatry, Queen’s University, Kingston, Canada
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Diana A. Jerusalinsky
4Laboratorio de Neuroplasticidad y Neurotoxinas, Instituto de Biología Celular y Neurociencia “Profesor Eduardo De Robertis”, Universidad de Buenos Aires/CONICET, Buenos Aires, Argentina
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Sergio T. Ferreira
1Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
13Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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  • For correspondence: ferreira@bioqmed.ufrj.br
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Abstract

Brain accumulation of soluble oligomers of the amyloid-β peptide (AβOs) has been implicated in synapse failure and memory impairment in Alzheimer’s disease. Here, we show that treatment with NUsc1, a single-chain variable fragment antibody (scFv) that selectively targets AβOs, prevents the inhibition of long-term potentiation in hippocampal slices and memory impairment induced by AβOs in mice. As a therapeutic approach for intracerebral antibody delivery, we developed an adeno-associated virus vector to drive neuronal expression of NUsc1 (AAV-NUsc1) within the brain. Transduction by AAV-NUsc1 induced NUsc1 expression and secretion in adult human brain slices, and inhibited AβO binding to neurons and AβO-induced loss of dendritic spine loss in primary rat hippocampal cultures. Treatment of mice with AAV-NUsc1 prevented memory impairment induced by AβOs and, importantly, reversed memory deficits in aged APPswe/PS1ΔE9 Alzheimer’s disease model mice. These results support the feasibility of gene-mediated immunotherapy using single-chain antibodies as a potential therapeutic approach in Alzheimer’s disease.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 13, 2022.
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AAV-mediated neuronal expression of a scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models
Maria Clara Selles, Juliana T.S. Fortuna, Magali C. Cercato, Luis Eduardo Santos, Luciana Domett, Andre L.B. Bitencourt, Mariane Favero Carraro, Amanda S. Souza, Helena Janickova, Jorge M. de Souza, Soniza Alves-Leon, Vania F. Prado, Marco A. M. Prado, Alberto L. Epstein, Anna Salvetti, Ottavio Arancio, William L. Klein, Adriano Sebollela, Fernanda G. De Felice, Diana A. Jerusalinsky, Sergio T. Ferreira
bioRxiv 2022.06.10.495369; doi: https://doi.org/10.1101/2022.06.10.495369
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AAV-mediated neuronal expression of a scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models
Maria Clara Selles, Juliana T.S. Fortuna, Magali C. Cercato, Luis Eduardo Santos, Luciana Domett, Andre L.B. Bitencourt, Mariane Favero Carraro, Amanda S. Souza, Helena Janickova, Jorge M. de Souza, Soniza Alves-Leon, Vania F. Prado, Marco A. M. Prado, Alberto L. Epstein, Anna Salvetti, Ottavio Arancio, William L. Klein, Adriano Sebollela, Fernanda G. De Felice, Diana A. Jerusalinsky, Sergio T. Ferreira
bioRxiv 2022.06.10.495369; doi: https://doi.org/10.1101/2022.06.10.495369

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