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

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. [Display omitted] In this work, Ferreira and colleagues show that targeting Aβ oligomers (AβOs) with an oligomer-specific single-chain variable-fragment antibody (NUsc1) delivered to the brain using an adeno-associated viral vector (AAV-NUsc1) rescues memory in AβO-infused WT mice and in aged APPswe/PS1ΔE9 Alzheimer’s disease model mice, supporting the feasibility of gene-mediated immunotherapy.