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

Mol Ther. 2023 Feb 1;31(2):409-419. doi: 10.1016/j.ymthe.2022.11.002. Epub 2022 Nov 11.

Abstract

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.

Keywords: AAV; Alzheimer’s disease; AβOs; NUsc1; immuno-gene therapy; memory; scFv.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / therapy
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Humans
  • Memory Disorders / genetics
  • Memory Disorders / therapy
  • Mice
  • Neurons / metabolism
  • Rats
  • Single-Chain Antibodies* / genetics
  • Single-Chain Antibodies* / metabolism
  • Synapses / metabolism

Substances

  • Single-Chain Antibodies
  • Amyloid beta-Peptides