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

Selles, M. C.; Fortuna, J. T. S.; Cercato, M. C.; Santos, L. E.; Domett, L.; Bitencourt, A. L. B.; Carraro, M. F.; Souza, A. S.; Janickova, H.; de Souza, J. M.; Alves-Leon, S.; Prado, V. F.; Prado, M. A. M.; Epstein, A. L.; Salvetti, A.; Arancio, O.; Klein, W. L.; Sebollela, A.; De Felice, F. G.; Jerusalinsky, D. A.; Ferreira, S. T.

doi:10.1101/2022.06.10.495369

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bioRxiv · 10.1101/2022.06.10.495369

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

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Abstract

Brain accumulation of soluble oligomers of the amyloid-{beta} peptide (A{beta}Os) has been implicated in synapse failure and memory impairment in Alzheimers disease. Here, we show that treatment with NUsc1, a single-chain variable fragment antibody (scFv) that selectively targets A{beta}Os, prevents the inhibition of long-term potentiation in hippocampal slices and memory impairment induced by A{beta}Os 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 A{beta}O binding to neurons and A{beta}O-induced loss of dendritic spine loss in primary rat hippocampal cultures. Treatment of mice with AAV-NUsc1 prevented memory impairment induced by A{beta}Os and, importantly, reversed memory deficits in aged APPswe/PS1{Delta}E9 Alzheimers disease model mice. These results support the feasibility of gene-mediated immunotherapy using single-chain antibodies as a potential therapeutic approach in Alzheimers disease.

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Selles, M. C., Fortuna, J. T. S., Cercato, M. C., Santos, L. E., Domett, L., Bitencourt, A. L. B., Carraro, M. F., Souza, A. S., Janickova, H., de Souza, J. M., Alves-Leon, S., Prado, V. F., Prado, M. A. M., Epstein, A. L., Salvetti, A., Arancio, O., Klein, W. L., Sebollela, A., De Felice, F. G., Jerusalinsky, D. A., Ferreira, S. T.. 2022-06-15. AAV-mediated neuronal expression of a scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models. https://doi.org/10.1101/2022.06.10.495369

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