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

Autor:	Selles MC; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; Skirball Institute for Biomolecular Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA., Fortuna JTS; Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil., Cercato MC; Laboratorio de Neuroplasticidad y Neurotoxinas, Instituto de Biología Celular y Neurociencia 'Profesor Eduardo De Robertis,' Universidad de Buenos Aires/CONICET, Buenos Aires 1121, Argentina., Santos LE; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil., Domett L; Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil., Bitencourt ALB; Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto 14049-900, Brazil., Carraro MF; Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto 14049-900, Brazil., Souza AS; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil., Janickova H; Department of Physiology & Pharmacology and Department of Anatomy & Cell Biology, Robarts Research Institute, The University of Western Ontario, London, ON N6A 5K8, Canada., Azevedo CV; Laboratório de Neurofisiologia, Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo 05508-000, Brazil., Campos HC; Laboratório de Neurofisiologia, Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo 05508-000, Brazil., de Souza JM; Division of Neurosurgery and Division of Neurology/Epilepsy Program, Clementino Fraga Filho University Hospital, Rio de Janeiro 21941-617, Brazil., Alves-Leon S; Division of Neurosurgery and Division of Neurology/Epilepsy Program, Clementino Fraga Filho University Hospital, Rio de Janeiro 21941-617, Brazil., Prado VF; Department of Physiology & Pharmacology and Department of Anatomy & Cell Biology, Robarts Research Institute, The University of Western Ontario, London, ON N6A 5K8, Canada., Prado MAM; Department of Physiology & Pharmacology and Department of Anatomy & Cell Biology, Robarts Research Institute, The University of Western Ontario, London, ON N6A 5K8, Canada., Epstein AL; UMR INSERM U1179-UVSQ, Université de Versailles Saint Quentin en Yvelines, 78180 Montigny-le-Bretonneux, France., Salvetti A; CIRI - Centre International de Recherche en Infectiologie, University of Lyon, Université Claude Bernard Lyon 1, INSERM, U1111, CNRS, UMR5308, ENS Lyon, 69007 Lyon, France., Longo BM; Laboratório de Neurofisiologia, Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo 05508-000, Brazil., Arancio O; Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA., Klein WL; Department of Neurobiology, Northwestern University, Evanston, IL 60201, USA., Sebollela A; Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto 14049-900, Brazil., De Felice FG; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; Centre for Neuroscience Studies, Department of Molecular and Biomedical Sciences & Department of Psychiatry, Queen's University, Kingston, ON K7L 3N6, Canada; D'Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil., Jerusalinsky DA; Laboratorio de Neuroplasticidad y Neurotoxinas, Instituto de Biología Celular y Neurociencia 'Profesor Eduardo De Robertis,' Universidad de Buenos Aires/CONICET, Buenos Aires 1121, Argentina., Ferreira ST; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; D'Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-170, Brazil. Electronic address: ferreira@bioqmed.ufrj.br.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2023 Feb 01; Vol. 31 (2), pp. 409-419. Date of Electronic Publication: 2022 Nov 11.
DOI:	10.1016/j.ymthe.2022.11.002
Abstrakt:	The accumulation of soluble oligomers of the amyloid-β peptide (AβOs) in the brain has been implicated in synapse failure and memory impairment in Alzheimer's disease. Here, we initially show that treatment with NUsc1, a single-chain variable-fragment antibody (scFv) that selectively targets a subpopulation of AβOs and shows minimal reactivity to Aβ monomers and fibrils, 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 spines in primary rat hippocampal cultures. Treatment of mice with AAV-NUsc1 prevented memory impairment induced by AβOs and, remarkably, reversed memory deficits in aged APPswe/PS1ΔE9 Alzheimer's disease model mice. These results support the feasibility of immunotherapy using viral vector-mediated gene delivery of NUsc1 or other AβO-specific single-chain antibodies as a potential therapeutic approach in Alzheimer's disease. Competing Interests: Declaration of interests A patent application covering the use of AAV-NUsc1 in Alzheimer’s disease has been filed with the USPTO (16/820,269; pending) by Northwestern University with S.T.F., W.L.K., D.A.J., A. Sebollela, and M.C.S. as named inventors. (Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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