Abstract
Brain accumulation of soluble oligomers of the amyloid-β peptide (AβOs) has been implicated in synapse failure and memory impairment in Alzheimer’s disease. Here, we show that treatment with NUsc1, a single-chain variable fragment antibody (scFv) that selectively targets AβOs, 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 spine loss in primary rat hippocampal cultures. Treatment of mice with AAV-NUsc1 prevented memory impairment induced by AβOs and, importantly, reversed memory deficits in aged APPswe/PS1ΔE9 Alzheimer’s disease model mice. These results support the feasibility of gene-mediated immunotherapy using single-chain antibodies as a potential therapeutic approach in Alzheimer’s disease.
Competing Interest Statement
The authors have declared no competing interest.
