Artículo
AAV-mediated neuronal expression of an scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models
Selles, Maria Clara; Fortuna, Juliana T.S.; Cercato, Magalí Cecilia
; Santos, Luis Eduardo; Domett, Luciana; Bitencourt, Andre L. B.; Favero Carraro, Mariane; Souza, Amanda S.; Janickova, Helena; Vieira Azevedo, Caroline; Correia Campos, Henrique; de Souza, Jorge M.; Alves-Leon, Soniza; Prado, Vania F.; Prado, Marco A.M.; Epstein, Alberto L.; Salvetti, Anna; Longo, Beatriz Monteiro; Arancio, Ottavio; Klein, William L.; Sebollela, Adriano; De Felice, Fernanda G.; Jerusalinsky, Diana Alicia
; Ferreira, Sergio Teixeira
Fecha de publicación:
11/2022
Editorial:
Nature Publishing Group
Revista:
Molecular Therapy
ISSN:
1525-0016
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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.
Palabras clave:
AAV
,
ALZHEIMER'S DISEASE
,
AΒOS
,
IMMUNO-GENE THERAPY
,
MEMORY
,
NUSC1
,
SCFV
Archivos asociados
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Identificadores
Colecciones
Articulos(IBCN)
Articulos de INST.DE BIOLO.CEL.Y NEURCS."PROF.E.DE ROBERTIS"
Articulos de INST.DE BIOLO.CEL.Y NEURCS."PROF.E.DE ROBERTIS"
Articulos(IQUIFIB)
Articulos de INST.DE QUIMICA Y FISICO-QUIMICA BIOLOGICAS "PROF. ALEJANDRO C. PALADINI"
Articulos de INST.DE QUIMICA Y FISICO-QUIMICA BIOLOGICAS "PROF. ALEJANDRO C. PALADINI"
Citación
Selles, Maria Clara; Fortuna, Juliana T.S.; Cercato, Magalí Cecilia; Santos, Luis Eduardo; Domett, Luciana; et al.; AAV-mediated neuronal expression of an scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models; Nature Publishing Group; Molecular Therapy; 31; 2; 11-2022; 409-419
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