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.
Original language | English (US) |
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Pages (from-to) | 409-419 |
Number of pages | 11 |
Journal | Molecular Therapy |
Volume | 31 |
Issue number | 2 |
DOIs | |
State | Published - Feb 1 2023 |
Keywords
- AAV
- Alzheimer's disease
- AβOs
- NUsc1
- immuno-gene therapy
- memory
- scFv
ASJC Scopus subject areas
- Drug Discovery
- Genetics
- Molecular Medicine
- Molecular Biology
- Pharmacology