| Texto completo | |
| Autor(es): Mostrar menos - |
Selles, Maria Clara
;
Fortuna, Juliana T. S.
;
Cercato, Magali C.
;
Santos, Luis Eduardo
;
Domett, Luciana
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Bitencourt, Andre L. B.
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Carraro, Mariane Favero
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Souza, Amanda S.
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Janickova, Helena
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Azevedo, Caroline Vieira
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Campos, Henrique Correia
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de Souza, Jorge M.
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Alves-Leon, Soniza
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Prado, Vania F.
;
Prado, Marco A. M.
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Epstein, Alberto L.
;
Salvetti, Anna
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Longo, Beatriz Monteiro
;
Arancio, Ottavio
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Klein, William L.
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Sebollela, Adriano
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De Felice, Fernanda G.
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Jerusalinsky, Diana A.
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Ferreira, Sergio T.
Número total de Autores: 24
|
| Tipo de documento: | Artigo Científico |
| Fonte: | MOLECULAR THERAPY; v. 31, n. 2, p. 11-pg., 2023-02-01. |
| Resumo | |
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) | |
| Processo FAPESP: | 14/25681-3 - Bases moleculares da toxicidade de oligômeros protéicos associados a amiloidoses do sistema nervoso |
| Beneficiário: | Adriano Silva Sebollela |
| Modalidade de apoio: | Auxílio à Pesquisa - Jovens Pesquisadores |