AAV-mediated neuronal expression of an 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, Caroline Vieira Azevedo, Henrique Correia Campos, Jorge M. de Souza, Soniza Alves-Leon, Vania F. Prado, Marco A.M. Prado, Alberto L. Epstein, Anna Salvetti, Beatriz Monteiro Longo, Ottavio Arancio, William L. KleinAdriano Sebollela, Fernanda G. De Felice, Diana A. Jerusalinsky, Sergio T. Ferreira*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)409-419
Number of pages11
JournalMolecular Therapy
Volume31
Issue number2
DOIs
StatePublished - Feb 1 2023

Keywords

  • AAV
  • Alzheimer's disease
  • AβOs
  • NUsc1
  • immuno-gene therapy
  • memory
  • scFv

ASJC Scopus subject areas

  • Drug Discovery
  • Genetics
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology

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