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

María Clara Sellés; Juliana T.S. Fortuna; Magalí Cecilia Cercato; Luís E. Santos; Luciana Domett; Andre L.B. Bitencourt; Mariane Favero Carraro; Amanda Santos de Souza; Helena Janíčková; Caroline Vieira Azevedo; Henrique Correia Campos; Jorge Marcondes de Souza; Soniza Vieira Alves‐Leon; Vânia F. Prado; Marco A. M. Prado; Alberto Luis Epstein; Anna Salvetti; Beatriz M. Longo; Ottavio Arancio; William L. Klein; Adriano Sebollela; Fernanda G. De Felice; Diana Alicia Jerusalinsky; Sergio Teixeira Ferreira

doi:10.1016/j.ymthe.2022.11.002

NeuroscienceMolecular TherapyNov 11, 2022

Peer-reviewed journal article

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

María Clara Sellés iD, Juliana T.S. Fortuna iD, Magalí Cecilia Cercato, Luís E. Santos iD, Luciana Domett, Andre L.B. Bitencourt, Mariane Favero Carraro iD, Amanda Santos de Souza iD, Helena Janíčková iD, Caroline Vieira Azevedo iD, Henrique Correia Campos iD, Jorge Marcondes de Souza iD, Soniza Vieira Alves‐Leon iD, Vânia F. Prado iD, Marco A. M. Prado iD, Alberto Luis Epstein iD, Anna Salvetti iD, Beatriz M. Longo iD, Ottavio Arancio iD, William L. Klein iD, Adriano Sebollela iD, Fernanda G. De Felice iD, Diana Alicia Jerusalinsky iD, Sergio Teixeira Ferreira iD

Abstract

Brain accumulation of soluble oligomers of the amyloid-{beta} peptide (A{beta}Os) has been implicated in synapse failure and memory impairment in Alzheimers disease. Here, we show that treatment with NUsc1, a single-chain variable fragment antibody (scFv) that selectively targets A{beta}Os, prevents the inhibition of long-term potentiation in hippocampal slices and memory impairment induced by A{beta}Os 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 A{beta}O binding to neurons and A{beta}O-induced loss of dendritic spine loss in primary rat hippocampal cultures. Treatment of mice with AAV-NUsc1 prevented memory impairment induced by A{beta}Os and, importantly, reversed memory deficits in aged APPswe/PS1{Delta}E9 Alzheimers disease model mice. These results support the feasibility of gene-mediated immunotherapy using single-chain antibodies as a potential therapeutic approach in Alzheimers disease.

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