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

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.