Memory recovery through gene therapy with an antibody fragment selective for Aβ oligomers in a model of Alzheimer’s disease in rats

Strong evidence supports the hypothesis that synapse damage and memory impairment in early Alzheimer Disease (AD) might be due to synaptic failure caused by amyloid beta oligomers (AβOs). The preclinical efficacy of a single-chain variable fragment (scFv) antibody NUsc1 that selectively targets a subpopulation of AβOs has been demonstrated; NUsc1 prevented inhibition of AβO-induced long-term potentiation in hippocampal slices and short-term memory impairment in mice. Since specific targeting of AβOs by NUsc1 can be a substantial improvement in target engagement and efficacy of AD therapy, an adeno-associated virus (AAV) vector was developed to drive neuronal expression of NUsc1 within the brain. AAV-NUsc1 rescued Short-Term Memory (STM) for object and conspecific interaction in mouse models of AD. In the McGill-R-Thy1-APP (Tg+/–) heterozygous transgenic McGill-R-Thy1-APP (Tg+/–) rat model of AD, progressive amyloid pathology is accompanied by cognitive impairment involving long-term memory (LTM) decline. LTM in a Novel-Object-Recognition (NOR) task was impaired in 4-month-old (Tg+/–) male rats, suggesting that they are unable to form/evoke such discriminative memories. Hence, it was investigated if AAV-NUsc1 treatment could rescued this memory. 10-12 weeks-old either Tg or wild type male rats were i.c.v. infused with AAV-NUsc1. Two months later, short-term exploratory behavior, habituation to an Open Field (OF), object discrimination and LTM for objects were assessed. AAV-NUsc1 treated Tg rats were able to successfully perform the task 24 h after training, denoting recovery of LT discrimination capacity and LTM formation. Wild type rats successfully performed the task either treated or not with AAV-NUsc1. In addition, exploration and short-term habituation to an open field was preserved in Tg+/– rats either treated or not. Our present and previous results suggest that AAVNUsc1 represents a significant advance in gene therapy, supporting the feasibility of immunotherapy using viral vector-mediated NUsc1 gene delivery as a potential therapeutic approach in AD

• Autores: Claudia Colettis, Natalia; Maria Victoria Oberholzer, Maria Victoria; Cercato, Magali; Habif, Martin; Clara Selles, Maria; Salas, Daniela; Sebollela, Adriano; Klein, William-L; Epstein, Alberto-L.; Salvetti, Anna; Ferreira, Sergio-T; Jerusalinsky, Diana
• Tipo de recurso: Article of journal
• Fecha de publicación: 2023
• Institución: Corporación Universidad de la Costa
• Repositorio: REDICUC - Repositorio CUC
• Idioma: eng
• OAI Identifier: oai:repositorio.cuc.edu.co:11323/12927
• Acceso en línea: https://hdl.handle.net/11323/12927; https://repositorio.cuc.edu.co
• Palabra clave: LTM; Alzheimer’s Disease; Gene therapy; scFv; Single chain antibody fragmen; Aβ oligomer; Memoria de larga duración MLD; Enfermedad de Alzheimer; Terapia génica; scFv; Fragmento de anticuerpo de cadena simple; Oligómeros Aβ
• Rights: openAccess
• License: Atribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)