Journal article
Allele-specific RNAi Mitigates Phenotypic Progression in a Transgenic Model of Alzheimer's Disease
Molecular therapy, Vol.17(9), pp.1563-1573
09/2009
DOI: 10.1038/mt.2009.123
PMCID: PMC2835271
PMID: 19532137
Abstract
Despite recent advances suggesting new therapeutic targets, Alzheimer's disease (AD) remains incurable. Aberrant production and accumulation of the Aβ peptide resulting from altered processing of the amyloid precursor protein (APP) is central to the pathogenesis of disease, particularly in dominantly inherited forms of AD. Thus, modulating the production of APP is a potential route to effective AD therapy. Here, we describe the successful use of an allele-specific RNA interference (RNAi) approach targeting the Swedish variant of APP (APPsw) in a transgenic mouse model of AD. Using recombinant adeno-associated virus (rAAV), we delivered an anti-APPsw short-hairpin RNA (shRNA) to the hippocampus of AD transgenic mice (APP/PS1). In short- and long-term transduction experiments, reduced levels of APPsw transprotein were observed throughout targeted regions of the hippocampus while levels of wild-type murine APP remained unaltered. Moreover, intracellular production of transfer RNA (tRNA)-valine promoter–driven shRNAs did not lead to detectable neuronal toxicity. Finally, long-term bilateral hippocampal expression of anti-APPsw shRNA mitigated abnormal behaviors in this mouse model of AD. The difference in phenotype progression was associated with reduced levels of soluble Aβ but not with a reduced number of amyloid plaques. Our results support the development of allele-specific RNAi strategies to treat familial AD and other dominantly inherited neurodegenerative diseases.
Details
- Title: Subtitle
- Allele-specific RNAi Mitigates Phenotypic Progression in a Transgenic Model of Alzheimer's Disease
- Creators
- Edgardo Rodríguez-Lebrón - Department of Neurology, University of MichiganCynthia M Gouvion - Department of Pharmacology and Toxicology, University of KansasSteven A Moore - Department of Pathology, University of IowaBeverly L Davidson - Department of Internal Medicine, University of IowaHenry L Paulson - Department of Neurology, University of Michigan
- Resource Type
- Journal article
- Publication Details
- Molecular therapy, Vol.17(9), pp.1563-1573
- Publisher
- Nature Publishing Group
- DOI
- 10.1038/mt.2009.123
- PMID
- 19532137
- PMCID
- PMC2835271
- ISSN
- 1525-0016
- eISSN
- 1525-0024
- Language
- English
- Date published
- 09/2009
- Academic Unit
- Pathology
- Record Identifier
- 9984047606702771
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