AAV-mediated neuronal expression of an scFv antibody selective for Af3 oligomers protects synapses and rescues memory in Alzheimer models

Author(s):Show less -

Selles, Maria Clara ; Fortuna, Juliana T. S. ; Cercato, Magali C. ; Santos, Luis Eduardo ; Domett, Luciana ; Bitencourt, Andre L. B. ; Carraro, Mariane Favero ; Souza, Amanda S. ; Janickova, Helena ; Azevedo, Caroline Vieira ; Campos, Henrique Correia ; 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 A. ; Ferreira, Sergio T.

• Document type: Journal article
• Source: MOLECULAR THERAPY; v. 31, n. 2, p. 11-pg., 2023-02-01.

Abstract

The accumulation of soluble oligomers of the amyloid-D pep-tide (ADOs) in the brain has been implicated in synapse fail-ure and memory impairment in Alzheimer's disease. Here, we initially show that treatment with NUsc1, a single-chain var-iable-fragment antibody (scFv) that selectively targets a subpopulation of ADOs and shows minimal reactivity to AD monomers and fibrils, prevents the inhibition of long-term potentiation in hippocampal slices and memory impairment induced by ADOs in mice. As a therapeutic approach for intracerebral antibody delivery, we developed an adeno-asso-ciated 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 ADO binding to neurons and ADO-induced loss of dendritic spines in primary rat hip-pocampal cultures. Treatment of mice with AAV-NUsc1 pre-vented memory impairment induced by ADOs and, remark-ably, reversed memory deficits in aged APPswe/PS1DE9 Alzheimer's disease model mice. These results support the feasibility of immunotherapy using viral vector-mediated gene delivery of NUsc1 or other ADO-specific single-chain an-tibodies as a potential therapeutic approach in Alzheimer's disease. (AU)

• FAPESP's process: 14/25681-3 - Molecular basis of the toxicity of protein oligomers associated to brain amyloidosis
• Grantee: Adriano Silva Sebollela
• Support Opportunities: Research Grants - Young Investigators Grants