PT  - JOURNAL ARTICLE
AU  - Maria Clara Selles
AU  - Juliana T.S. Fortuna
AU  - Magali C. Cercato
AU  - Luis Eduardo Santos
AU  - Luciana Domett
AU  - Andre L.B. Bitencourt
AU  - Mariane Favero Carraro
AU  - Amanda S. Souza
AU  - Helena Janickova
AU  - Jorge M. de Souza
AU  - Soniza Alves-Leon
AU  - Vania F. Prado
AU  - Marco A. M. Prado
AU  - Alberto L. Epstein
AU  - Anna Salvetti
AU  - Ottavio Arancio
AU  - William L. Klein
AU  - Adriano Sebollela
AU  - Fernanda G. De Felice
AU  - Diana A. Jerusalinsky
AU  - Sergio T. Ferreira
TI  - AAV-mediated neuronal expression of a scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models
AID  - 10.1101/2022.06.10.495369
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.06.10.495369
4099  - http://biorxiv.org/content/early/2022/06/13/2022.06.10.495369.short
4100  - http://biorxiv.org/content/early/2022/06/13/2022.06.10.495369.full
AB  - 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 StatementThe authors have declared no competing interest.